October 27, 2005

Susan Hayward

97 Jamestowne Way, Unit 65

Taylors, SC 29687

Food and Drug Administration

Division of Documents Management (HFA-305)

Docket No. 2005N-0404

5630 Fishers Lane

Room 1061

Rockville, MD 20852

RE: Public Comment AGAINST Gonadotroptin Agonist Testing in Disorders of
Puberty

DOCKET NUMBER 2005N-0404

Dear Sir/Madam:

Please accept this letter as formal opposition to the proposed
above-mentioned medical study at the University of Chicago Hospitals
General Clinical Research Facility. I base my decision on personal
experience as a former consumer of the drug Lupron, study of it's
effects on other patients, how the manufacturer conducts business, their
history of legal and political maneuvers, and experiences with the
medical community.

It is my understanding that the FDA position on the Lupron Issue is that
there are no viable alternatives for treatments. I would hope your
agency would focus as much time, money and effort on prevention as you
do study. Why is there such a high incidence of hormonal disorders like
precocious puberty and endometriosis? After looking at this issue for
many years, I have come to the conclusion that our answers lie in the
food supply. That would explain why formula manufacturers (one of them
being Abbott Laboratories, the manufacturer of Similac, and also the
partner corporation producing Lupron), and the National Cattlemen's Beef
Association would both have such a vested interest in the American
Academy of Pediatrics. As long as the medical community is benefitting
from these organizations, you can expect promotion and tolerance of any
products whether they be safe for consumers or not, and a hands off
approach to criticism. The American Public deserves better than
influence peddling, and our children need protection. I invite you to
review the attachments documenting my allegations.

I didn't start out as an outspoken critic of the pharmaceutical
industry, but circumstances forced me to educate myself about my
situation when the medical community refused to diagnose my syndrome.
You don't become a mechanic when you need your car repaired, but
hundreds and perhaps thousands of former Lupron patients are being
forced into medical research in order to diagnose themselves with rare
diseases such as Hashimoto's Encephilitus, Autoimmune Inner Ear Disease,
Grave's Disease, Lupus, etc. Often, we patients get misdiagnosed with
something simple like allergies or junk diagnosis of chronic fatigue and
fibromyalgia. We become disabled and lose our quality of life as we knew
it, financially, familial and socially. Most of us are too sick to fight
and become shut ins. We have lost our voice on the internet because
websites have been purchased by corporations who hire moderators that
silence us. The lack of response to the upcoming deadline for public
comments is a testimony to how good a job they have done in keeping us
from being vocal. The National Lupron Victims Network had over 1 million
hits before it was taken down mysteriously a few years ago. Where did
the members go? Did they get well again? I didn't, so I would think they
are ill. The FDA had many thousands of Adverse Condition Reports on file
for Lupron prompting the black box relabelling. Don't they have any
place in your decision to inject this drug into children? Why fill out
forms if they get ignored?

Allow me to give you my opinion on the whole matter of Lupron. I believe
Taketa and Abbott Labs formed TAP as a hedge for future lawsuits,
thereby protecting the parent companies. TAP can go out of business when
the truth about Lupron finally catches up with them, and Taketa/Abbott
both walk away after making billions in profits. I must commend their
lawyers because it was a brilliant move. This country has a history of
product liability where the manufacturer is forced into bankruptcy, so
the incorporation of TAP was a very smart business decision as profits
can be siphoned off to the parent company.

May I remind you that TAP has a history of fraudulent activity and holds
the record in this country for the highest fine levied against a drug
manufacturer. There was widespread corruption with employees, and
doctors were bribed with free samples billable to patients and insurance
companies along with other perks. My former gynocologist was a
researcher and accepted money from TAP to fund his work. Do you think he
had my best interests at heart? Which side do you think he'd join, mine
or TAP's? Allow me answer that for you. He chose TAP. He saw I had an
abnormal thyroid test while on Lupron and instead of notifying me as
suggested by the lab, he filed it. His strategy to avoid a lawsuit was
successful because the statute of limitations passed before I could
prove a case, similar most patient\'s legal problem. The patients who do
file suit generally have the record sealed at TAP's request making it
more difficult for other claimants to obtain documents. The lawyers take
most of the proceeds of settled cases in fees and expenses, leaving
patients with destroyed lives and little or no compensation.

This legal dilemma creates a climate where patients are viewed as
adversaries because the doctors pay the price for lawsuits in the form
of higher malpractice insurance rates. The doctors and their
professional associations side with the drug manufacturers, and the
patients get classed on the side of lawyers who take advantage of them.
We lose on all fronts; not only are we ill but we can\'t get the support
of our doctors to diagnose and treat us. My only option is to cry out a
warning to other people who may use this drug. There are many more
issues I could expand on and give you examples of how the media has been
manipulated and how paid lobbyists control politicians, etc., but I
believe you understand my point.

Pub Med 14558924 published in Thyroid 8/13/03 makes this recommendation
\"All patients who are to receive GnRH analogue therapy should be
examined for antithyroid antibodies and family history of autoimmune
thyroid disease, and should be followed accordingly.\" The Journal of
Pediatrics countered this conclusion by claiming it was an iscolated
case. I disagree and am living proof that the conclusion was correct in
PMID 14558924. The doctor could have just asked, is there a history of
thyroid issues in your family? My mother had a thyroid condition and
that would have eliminated me as a prospective patient. Isn\'t that the
root of the problem, money? If TAP loses a market share to people with a
family history of autoimmune problems their profits may be reduced?
Should the medical societies devulge the truth do they get retalliation
in the form of less donations for their own agenda?

This brings me to what I want from you, and that's to rethink injecting
WELL children as a control group with this drug. Lupron is dangerous and
TAP has not been forthcoming with information about this drug. Until
they demonstrate a more open approach in the way they conduct business,
I think it's a huge mistake to use children as test subjects. The
package inserts are evasive; referring to other inserts and purposely
downplaying the risks. I look at the parent's guide TAP distributes and
it discloses very little. On page 7 of the Lupron PED insert it says,
"Discontinuation of Lupron Depot--Ped should be considered before age 11
for females and age 12 for males". Why isn't that in the parent's guide?
Are they expected to wade through 7 pages of pharmacology in order to
figure out the child shouldn't be taking it anymore? I've seen these
kids on Lupron until 14. There are Pub-Med Studies showing the bone loss
so severe that screws had to be inserted to support the hip, but they
continued Lupron. What are the doctors getting out of this drug that
they are so pro-Lupron? Why aren't we getting alternatives to such a
dangerous drug? Can you imagine what it feels like for a parent to
discover they gave their child something that made them very ill? There
is an over emphasis on a reduction of side effects once the drug wears
off, but it\'s not true in many cases like my own. The changes Lupron
makes are permanent in many cases, and we are being ignored.

One area I really want to bring your attention to is depression. Lupron
induces severe depression in most patients. On page 16 of the Lupron
Depot 3.75 Package Insert (note that it\'s page 16 of 18) under
Postmarketing it says, mood swings, suicidal ideation and ATTEMPT. These
are REPORTED adverse events. How are children going to be safe when they
are so young most won't even be diagnosed for depression that early? The
ones who do go on to develop the autoimmune problems that are downplayed
in the same Postmarketing section under Localized Reactions, have only
one method of treatment according to the latest studies, prednisone.
Anyone familiar with prednisone knows these patients are highly
susceptible to mood swings. When you compound the psychological aspects
with the treatment of autoimmune problems, it's a huge challenge to
manage.

The reason this Lupron issue has always been so personal to me when it
comes to children is because I know the memory loss that occurs first
hand. These children will never have the chance at a normal education
using this drug. I describe the loss like holes in Swiss Cheese, some
long-term, some short. It takes years for all the diseases and
conditions to be discovered. The damage to the endocrine system is
permanent for many people, and their lives and occupations are
destroyed. It happened to me when I was 37 and I had a chance to live a
little before the problems. How can this be allowed to happen to
innocent children? I can't. I have to speak out because it will be on my
conscience the rest of my life if I don't defend them. If you had a
child who was sick, could you live with yourself that the treatment did
more harm than good? Wouldn\'t you be angry if you found out all it
would have taken was a blood test or medical history to avoid it?

Over and over the package inserts say no study was done. Why is it that
new studies are funded, but never follow up long-term with people who
took the drug? Page 2 of the 3.75 insert says "No pharmacokinetic-based
drug-drug interations studies have been conducted with Lupron Depot."
Instead they offer an assumption based on science as an explanation.
Why? How long have they been injecting men and women and they still have
no idea how other drugs react with it? Out of the billions in profit
they've made they couldn't send out a questionnaire? We have no idea how
many people got sick from Lupron out of the millions of injections
because nobody asks. There is no financial incentive for TAP to do
studies on anything but new markets. Are you aware they are giving
Lupron to children for autism? I suspect this is why there's a push to
get the precocious puberty off-label use sanctioned, because the next
step will be the autism emerging market. Who is minding the store? Who
is watching out for us? These are people's lives being destroyed.
Without Lupron, what happens? The NLVN said the kids eventually end up
the same without the drug. Why poison them in the process? Can't TAP get
more than 22 children (page 2 PED insert) to study who took the Lupron
than recruiting healthy children as a control? Why not ask how those 22
kids are doing now before experimenting with more people? It just
doesn't make any sense to me.

I've done my best to make my point that there's more involved here than
just treating a childhood problem. Physicians need more education than a
sales rep's marketing plan to stop further abuses with this drug.
Patients can't get the care they need because doctors don't realize what
kinds of problems we suffer. I've had arthritus for years and still test
negative. My x-rays show the arthritus but Lupron causes a chameleon
type of syndrome from fluctuations in the thryoid, pituitary and
hypothalmus. I have no medical background, so it's very difficult for me
to explain. All I know is I have conditions like gout that test
negative, but the minute I eat shellfish my ankle swells. I test
negative for lupus, but have had fluid draining out of my ear for 4
years and the swollen eustacian tubeonly improves with prednisone. Is it
possible I have some form of silent lupus? Autoimmune ear disease has an
incidence of 200 out of 1,000,000 so it\'s extremely rare. The only
doctor who can diagnose me is in another state and there are very few of
these specialists in the entire country. What I\'m saying is that I am
still looking for answers to the damage Lupron caused several years
later. I manage so many diseases and conditions now that I stopped
counting at 10, but 14 years ago I had 1 and that was endometriosis. The
financial cost of my disability is over \$1,000,000 in lost wages and
productivity. Imagine what the cost of medical care is on top of that,
not to mention quality of life issues. All of this could have been
avoided had my doctor made a choice that my family medical history put
me at risk for complications due to Lupron. Are you willing to create a
whole new generation of sufferers with this study, especially children
who don\'t have the condition being treated?

Hopefully you will consider what I'm trying to convey and think of those
precious children and their parents when making your decision. My hope
is that the problems I faced will somehow help others when they become
ill and can't find answers. I will never give up trying to regain my
health or the ambition of being able to function again. It's a terribly
lonely predicament to be a prisoner in a sick body, withdrawn from the
world, and never receiving compensation for a drug company's lies and
legal manipulation. TAP knows the truth, and now you do too. My wish is
that the spirit of the Lord guide you in your decision.

Respectfully,

Susan Hayward

SH/

Exhibits: I. Non-Profit Organizations Receiving Corporate Funding

II\. Pub-Med ID #15001954

III\. Journal of Pediatrics Response to PMID #15001954

IV\. Pub-Med ID #14558924

V. Pub-Med ID #11228054

VI\. Pub-Med ID #9230649

VII\. A Parent\'s Guide To Precocious Puberty

VIII\. Lupron Depot-Ped Package Insert

IX\. Lupron Depot 3.75 Package Insert

Exhibit I.

+----------------------------------------------------------------------+
| **Non-Profit Organizations Receiving Corporate Funding**             |
+----------------------------------------------------------------------+
| [[Index of Non-Profit Organizations Receiving Corporate              |
| Funding](/integrity/nonprofits/index.html)]{.underline}              |
+----------------------------------------------------------------------+
| \                                                                    |
| **AMERICAN ACADEMY OF PEDIATRICS**                                   |
+----------------------------------------------------------------------+
| "Friends of Children Fund" Annual Report, July 1, 1996 - June 30,    |
| 1997, indicates \$2.085 million in funding from corporations. Donors |
| include Procter & Gamble, Gerber, Infant Formula Council, McNeil     |
| Consumer Products Company, National Cattlemen's Beef Association,    |
| Johnson & Johnson Consumer Products, Abbott Laboratories,            |
| Wyeth-Lederle Vaccine & Pediatrics, Mead Johnson Nutritionals,       |
| SmithKline Beecham Pharmaceuticals, Schering Corp., Rhone-Poulenc    |
| Rorer, Food Marketing Institute, Sugar Association, International    |
| Food Information Council, Merck Vaccine Division, and others.        |
|                                                                      |
| Formula manufacturers "donate \$1 million annually to the American   |
| Academy of Pediatrics in the form of a renewable grant that has      |
| already netted the AAP \$8 million. The formula industry also        |
| contributed at least \$3 million toward the building costs of the    |
| AAP headquarters." (Mothering magazine, July-August, p.60; refers to |
| a book *Milk, Money and Madness* by Naomi Baumslag and Dia L.        |
| Michels (Westport, Conn.: Bergin and Garvey, 1995, p. 172))          |
|                                                                      |
| According to a New York Times article, the Ross Products Unit of     |
| Abbott Laboratories, the maker of Similac infant formula, purchased  |
| 300,000 copies of the AAP's "New Mother's Guide to Breastfeeding"    |
| with Ross' logo and name on them. In addition, "Ross, McNeil and     |
| Johnson & Johnson were the top three corporate supporters of the     |
| academy's \$65 million operating budget\...each giving \$500,000 or  |
| more." (New York Times, 9/18/02, C1)                                 |
+----------------------------------------------------------------------+

\
EXHIBIT II.

**Autoimmune thyroiditis during leuprolide acetate treatment.**\
\
**[[Eyal
O](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Eyal+O%22%5BAuthor%5D)]{.underline}**,
**[[Rose
SR](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Rose+SR%22%5BAuthor%5D)]{.underline}**.\
\
Division of Pediatric Endocrinology, Cincinnati Children\'s Hospital
Medical Center, University of Cincinnati, Cincinnati, Ohio 45229-3039,
USA. Susan.Rose@cchmc.org\
\
Autoimmune thyroiditis developed in a 9-year-old girl with precocious
puberty approximately 8 months after initiation of Leuprolide acetate
therapy. In addition, gonadotropin concentrations as measured by
radioimmunoassay appeared high. Treatment with levothyroxine, in
addition to continued Leuprolide acetate treatment, resolved
gonadotropin elevation and hypothyroidism.\
\
Publication Types:

· [[Case
Reports](javascript:AL_get(this, 'ptyp', 'Case Reports');)]{.underline}

\
PMID: 15001954 \[PubMed - indexed for MEDLINE\]

EXHIBIT III.

**The role of leuprolide acetate therapy in triggering auto-immune
thyroiditis**

[[Michael Haller](#)]{.underline}, MD, [[Desmond
Schatz](#)]{.underline}, MD

**Article Outline**

• [[References](#bibliography)]{.underline}

• [[Copyright](#)]{.underline}

*To the Editor:*

We read with interest the report by Eyal and Rose regarding the
occurrence of autoimmune hypothyroidism in a 9-year-old girl with
precocious puberty who was treated with the gonadaropin-releasing
hormone (GnRH) agonist, leuprolide acetate, for approximately 8
months.[[1](#bib1)]{.underline} From this single case report, the
authors suggested an association of leuprolide acetate with autoimmune
thyroiditis and recommended thyroid stimulating hormone (TSH) screening
before and 6 to 8 months into treatment. We believe the authors\'
conclusions are overstated.

The authors suggest that autoimmune disease is "related to potential
immunostimmulatory properties of GnRH agonists independent of gonadal
steroids," as stated in the paper. The reference cited in support of the
authors\' suggestion states "there is little evidence for direct immune
actions of gonadatropins" and "it appears that the studies demonstrating
immunostimulatory properties of GnRH were done exclusively in female
rats."[[2](#bib2)]{.underline} No other accompanying organ specific or
non-organ specific autoimmune disorders were reported. In the case
presented, there was no documentation of autoantibody status before the
start of leuoprolide therapy. In addition, the patient had a sibling
with primary hypothyroidism and a family member with type I diabetes
(T1DM). Clustering of autoimmune thyroid disease in families is well
described.[[3-5](#bib3)]{.underline} Furthermore, relatives of patients
with T1DM have a much higher incidence of thyroid autoimmunity (up to
25%).[[6](#bib6)]{.underline} When added to the significant female to
male predominance of thyroid disease, it is likely that these factors
played a much more significant role in the patient\'s development of
thyroid disease than leuprolide acetate therapy.

Based on this single case report, we therefore disagree with the
suggestion that leuprolide acetate treatment requires thyroid screening.
The use of primary autoantibody screening vs primary thyroid function
screening also must be addressed. Screening always involves additional
cost and, often, additional stress. Well-designed studies should be
conducted before such recommendations are made. Outside a research
setting, patients should be screened for autoimmune thyroid disease only
on the basis of well-established risk factors and clinical presentation.

EXHIBIT IV.

**Possible induction of Graves\' disease and painless thyroiditis by
gonadotropin-releasing hormone analogues.**\
\
**[[Amino
N](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Amino+N%22%5BAuthor%5D)]{.underline}**,
**[[Hidaka
Y](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Hidaka+Y%22%5BAuthor%5D)]{.underline}**,
**[[Takano
T](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Takano+T%22%5BAuthor%5D)]{.underline}**,
**[[Tatsumi
KI](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Tatsumi+KI%22%5BAuthor%5D)]{.underline}**,
**[[Izumi
Y](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Izumi+Y%22%5BAuthor%5D)]{.underline}**,
**[[Nakata
Y](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Nakata+Y%22%5BAuthor%5D)]{.underline}**.\
\
Department of Laboratory Medicine, Osaka University Graduate School of
Medicine, Suita, Osaka, Japan. namino@labo.med.osaka-u.ac.jp\
\
Prolonged administration of gonadotropin-releasing hormone (GnRH)
analogues induce a decrease in serum estrogen level, which may aggravate
subclinical or mild autoimmune thyroid disease. Two patients developed
Graves\' thyrotoxicosis in association with an increase in
anti-thyrotropin (TSH) receptor antibody activities at 4 months after
initiation of buserelin acetate. GnRH analogue therapy was discontinued
at the time of diagnosis but it took more than 2 years of methimazole
therapy to obtain remission of Graves\' disease. Another patient
developed painless thyroiditis in association with an increase in
antithyroid microsomal antibodies at 4 months after initiation of
leuprolide acetate. These results indicate that GnRH analogues possibly
induce clinical onset of Graves\' thyrotoxicosis or destruction-induced
thyrotoxicosis. Clinicians should be aware of this phenomenon. All
patients who are to receive GnRH analogue therapy should be examined for
antithyroid antibodies and family history of autoimmune thyroid disease,
and should be followed accordingly.

EXHIBIT V.

**Transient thyrotoxicosis and hypothyroidism following administration
of the GnRH agonist leuprolide acetate.**\
\
**[[Kasayama
S](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Kasayama+S%22%5BAuthor%5D)]{.underline}**,
**[[Miyake
S](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Miyake+S%22%5BAuthor%5D)]{.underline}**,
**[[Samejima
Y](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Samejima+Y%22%5BAuthor%5D)]{.underline}**.\
\
Department of Molecular Medicine, Osaka University Graduate School of
Medicine, Suita-city, Japan.\
\
A 45-year-old women with chronic idiopathic thrombocytopenic purpura was
given monthly injections of the GnRH agonist leuprolide acetate for the
treatment of uterine leiomyoma. Two weeks after the fifth injection, she
showed mild symptoms of thyrotoxicosis. At that time, serum thyroxin
(T4) and triiodothyronine (T3) levels were elevated whereas TSH level
was suppressed. Anti-thyroglobulin (anti-Tg) and anti-thyroid peroxidase
(anti-TPO) antibodies were positive, whereas TSH binding inhibitory
immunoglobulin (TBII) was undetectable. Two months later, serum T4 and
T3 levels spontaneously decreased below the normal ranges. Five months
after the onset of the disease, they returned to normal without any
treatment. Anti-TPO and anti-Tg antibodies gradually decreased during
the clinical course. Thus, the present case was indicated to be an
instance wherein silent thyroiditis developed after leuprolide acetate
administration. This is the first report to demonstrate the association
of thyroid disorder with leuprolide injection.

EXHIBIT VI.

**Anxiety and mood disorders associated with gonadotropin-releasing
hormone agonist therapy.**\
\
**[[Warnock
JK](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Warnock+JK%22%5BAuthor%5D)]{.underline}**,
**[[Bundren
JC](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Bundren+JC%22%5BAuthor%5D)]{.underline}**.\
\
Department of Psychiatry, University of Oklahoma Health Sciences Center
at Tulsa 74129-1077, USA.\
\
Gonadotropin-releasing hormone (GnRH) agonists are synthetic derivatives
of the native decapeptide produced by the hypothalamus. These agents
cause a reversible suppression of the synthesis and release of
luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by the
anterior pituitary gland. With GnRH agonist therapy, there is a
resulting loss of endogenous ovarian gonadotropin stimulation and a
severe hypo-estrogen state consistent with castrate levels of estrogen.
Recently, GnRH agonists such as leuprolide and goserelin have been noted
to be effective in treating mild to severe endometriosis. Side effects
of these agents are consistent with the physiological effects of ovarian
suppression, such as vasomotor instability, vaginal dryness, and
headaches. However, despite some reports of emotional lability as an
adverse effect of GnRH agonists, it appears that the occasional, rather
severe psychiatric consequences of these agents are underappreciated. In
this article, we present the case reports of 4 women of reproductive age
with no prior psychiatric history who were treated with a GnRH agonist
for endometriosis. These women developed symptoms consistent with
various psychiatric disorders, including panic disorder and major
depression with and without psychotic features. Three of these patients
were given sertraline while on GnRH agonist therapy, which improved
their mood and anxiety symptoms. Women undergoing GnRH agonist therapy
may provide a model with which to investigate mood disorders during the
perimenopausal stage of life.

EXHIBIT VII.

A PARENT'S

GUIDE

TO

PRECOCIOUS

PUBERTY

LUPRON DEPOT-PED®

LEUPROLIDE ACETATE FOR DEPOT SUSPENSION

INTRODUCTION

All children develop body changes at puberty, but sometimes these normal
changes occur

too soon. This condition is called "precocious puberty." It should be
evaluated and

probably treated. A child who has the normal teenage-type growth spurt
too soon will

also stop growing too soon and will not be as tall an adult as he or she
could have been.

Also, these children are often embarrassed and confused by their early
development; this

could lead to social difficulties.

WHAT IS PRECOCIOUS

PUBERTY?

Precocious puberty occurs when girls under the age of 8 or boys under
the age of 9 begin

to develop signs of sexual maturity. This happens to about one child in
every 5,000 to

10,000.

SIGNS AND SYMPTOMS

Girls develop breasts and may have monthly periods.

The penis and testicles of boys grow larger.

Behavior may change; children may become aggressive or moody.

Pubic hair grows in both sexes.

Children may have oily skin and/or acne.

Your child may be the tallest in the class; there is a sudden growth
spurt like that usually

seen in teenagers.

WHY DOES IT HAPPEN?

In most cases, there is no special reason for your child's early
development. It is not

caused by anything we do and is not necessarily passed on from parents
to children.

However, there may be some physical problem, like a tumor, causing
precocious puberty;

this would require other treatment. Your doctor will perform tests to
rule out some

possible physical causes.

HOW WILL

LUPRON DEPOT-PED® HELP?

Lupron Depot-PED is a hormone-like agent. It is given by injection once
a month to

adjust your child's body clock.

Your child will stop making some hormones at adult levels.

Pubertal changes (pubic hair, girl's period, breasts, etc.) should stop
and may even

become less obvious.

Growth rate becomes more normal.

When it's right for your child, your doctor will stop administering the
shots and puberty

will begin again.

REGULAR INJECTIONS

ARE IMPORTANT!

For best results, your child should have the right amount of Lupron
Depot-PED in his or

her body at all times. If you miss a shot or are a week late, your
child's pubertal

development could begin again.

STAY ON SCHEDULE!

Keep your appointments; this is absolutely necessary for success.

Irregular dosing could restart the maturation process.

WHEN TO CALL YOUR DOCTOR

The following items are not necessarily problems, but your doctor will
want to know

about them. Call your doctor if:

There is redness or puffiness of the skin around where the shot was
given.

Pubertal changes continue.

Your daughter has a period, especially after the first month.

You have problems keeping the monthly injection schedule.

Anything else happens that causes you concern.

THINGS TO MENTION AT YOUR

NEXT APPOINTMENT:

If your child has substantial mood swings (write down the date this
happens)

Any behavioral changes (boys may become aggressive; girls may become
moody)

PARENT SUPPORT GROUP

The MAGIC Foundation (Major Aspects of Growth in Children) provides free
brochures,

growth charts, children's newsletters, and information on endocrine
disorders affecting

children's growth and development. The MAGIC Foundation at
1-800-362-4423 can also

put you in touch with other parents who are raising children with
precocious puberty.

This patient education brochure is not intended to be a substitute for
information

provided to you by your physician or provided to your physician by TAP

Pharmaceuticals Inc.

You should discuss with your physician any questions you have about the
diagnosis and

treatment of precocious puberty.

This information is provided as a service of TAP Pharmaceuticals Inc.

TAP Pharmaceuticals Inc.

Lake Forest, IL 60045

(Nos. 2108, 2282, 2440)

03-5020-R5; Revised: December, 2000

®--Registered Trademark

Ó2000 TAP Pharmaceutical Products Inc. Printed in U.S.A.

EXHIBIT VIII.

LUPRON DEPOT-PED PACKAGE INSERT

LUPRON DEPOT-PED Package InsertPage 1 of 9LUPRON DEPOT-PED®(leuprolide
acetate for depot suspension)7.5 mg, 11.25 mg and 15 mgRx
onlyDESCRIPTIONLeuprolide acetate is a synthetic nonapeptide analog of
naturally occurring gonadotropin-releasing hormone (GnRH or LH-RH). The
analog possesses greater potency than the naturalhormone. The chemical
name is
5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide
acetate (salt) with the following structuralformula:LUPRON DEPOT-PED is
available in a prefilled dual-chamber syringe containing
sterilelyophilized microspheres which, when mixed with diluent, become a
suspension intended as asingle intramuscular injection.The front chamber
of LUPRON DEPOT-PED 7.5 mg, 11.25 mg, and 15 mg prefilled dual-chamber
syringe contains leuprolide acetate (7.5/11.25/15 mg), purified
gelatin(1.3/1.95/2.6 mg), DL-lactic and glycolic acids copolymer
(66.2/99.3/132.4 mg), and D-mannitol(13.2/19.8/26.4 mg). The second
chamber of diluent contains carboxymethylcellulose sodium(5 mg),
D-mannitol (50 mg), polysorbate 80 (1 mg), water for injection, USP, and
glacial aceticacid, USP to control pH.During the manufacture of LUPRON
DEPOT-PED, acetic acid is lost, leaving the peptide.CLINICAL
PHARMACOLOGYLeuprolide acetate, a GnRH agonist, acts as a potent
inhibitor of gonadotropin secretion whengiven continuously and in
therapeutic doses. Human studies indicate that following an
initialstimulation of gonadotropins, chronic stimulation with leuprolide
acetate results in suppressionor "downregulation" of these hormones and
consequent suppression of ovarian and testicularsteroidogenesis. These
effects are reversible on discontinuation of drug therapy.Leuprolide
acetate is not active when given orally.Pharmacokinetics\
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LUPRON DEPOT-PED Package InsertPage 2 of 9Absorption Following a single
LUPRON DEPOT 7.5 mg injection to adult patients, meanpeak leuprolide
plasma concentration was almost 20 ng/mL at 4 hours and then declined
to0.36 ng/mL at 4 weeks. However, intact leuprolide and an inactive
major metabolite could notbe distinguished by the assay which was
employed in the study. Nondetectable leuprolideplasma concentrations
have been observed during chronic LUPRON DEPOT 7.5 mgadministration, but
testosterone levels appear to be maintained at castrate
levels.Distribution The mean steady-state volume of distribution of
leuprolide following intravenousbolus administration to healthy male
volunteers was 27 L. In vitro binding to human plasmaproteins ranged
from 43% to 49%.Metabolism In healthy male volunteers, a 1 mg bolus of
leuprolide administered intravenouslyrevealed that the mean systemic
clearance was 7.6 L/h, with a terminal elimination half-life
ofapproximately 3 hours based on a two compartment model.In rats and
dogs, administration of14C-labeled leuprolide was shown to be
metabolized tosmaller inactive peptides, a pentapeptide (Metabolite I),
tripeptides (Metabolites II and III) anda dipeptide (Metabolite IV).
These fragments may be further catabolized.The major metabolite (M-I)
plasma concentrations measured in 5 prostate cancer patientsreached
maximum concentration 2 to 6 hours after dosing and were approximately
6% of thepeak parent drug concentration. One week after dosing, mean
plasma M-I concentrations wereapproximately 20% of mean leuprolide
concentrations.Excretion Following administration of LUPRON DEPOT 3.75
mg to 3 patients, less than 5%of the dose was recovered as parent and
M-I metabolite in the urine.Special Populations The pharmacokinetics of
the drug in hepatically and renally impairedpatients have not been
determined.CLINICAL STUDIESIn children with central precocious puberty
(CPP), stimulated and basal gonadotropins arereduced to prepubertal
levels. Testosterone and estradiol are reduced to prepubertal levels
inmales and females respectively. Reduction of gonadotropins will allow
for normal physical andpsychological growth and development. Natural
maturation occurs when gonadotropins returnto pubertal levels following
discontinuation of leuprolide acetate.The following physiologic effects
have been noted with the chronic administration ofleuprolide acetate in
this patient population.1. Skeletal Growth. A measurable increase in
body length can be noted since theepiphyseal plates will not close
prematurely.2. Organ Growth. Reproductive organs will return to a
prepubertal state.3. Menses. Menses, if present, will cease.In a study
of 22 children with central precocious puberty, doses of LUPRON DEPOT
weregiven every 4 weeks and plasma levels were determined according to
weight categories assummarized below:\
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LUPRON DEPOT-PED Package InsertPage 3 of 9Patient WeightRange (kg)Group
WeightAverage (kg)Dose (mg)Trough Plasma Leuprolide LevelMean ±SD
(ng/mL)\*20.2 - 27.022.77.50.77±0.03328.4 - 36.832.511.251.25±1.0639.3 -
57.544.215.01.59±0.65\*Group average values determined at Week 4
immediately prior to leuprolide injection. Drug levels at 12 and24 weeks
were similar to respective 4 week levels.INDICATIONS AND USAGELUPRON
DEPOT-PED is indicated in the treatment of children with central
precociouspuberty. Children should be selected using the following
criteria:1. Clinical diagnosis of CPP (idiopathic or neurogenic) with
onset of secondary sexualcharacteristics earlier than 8 years in females
and 9 years in males.2. Clinical diagnosis should be confirmed prior to
initiation of therapy:• Confirmation of diagnosis by a pubertal response
to a GnRH stimulation test. Thesensitivity and methodology of this assay
must be understood.• Bone age advanced one year beyond the chronological
age.3. Baseline evaluation should also include:• Height and weight
measurements.• Sex steroid levels.• Adrenal steroid level to exclude
congenital adrenal hyperplasia.• Beta human chorionic gonadotropin level
to rule out a chorionic gonadotropin-secreting tumor.•
Pelvic/adrenal/testicular ultrasound to rule out a steroid secreting
tumor.• Computerized tomography of the head to rule out intracranial
tumor.CONTRAINDICATIONSLUPRON DEPOT-PED is contraindicated in women who
are or may become pregnant whilereceiving the drug. When administered on
day 6 of pregnancy at test dosages of 0.00024,0.0024, and 0.024 mg/kg
(1/1200 to 1/12 of the human pediatric dose) to rabbits,LUPRON DEPOT
produced a dose-related increase in major fetal abnormalities.
Similarstudies in rats failed to demonstrate an increase in fetal
malformations. There was increasedfetal mortality and decreased fetal
weights with the two higher doses of LUPRON DEPOT inrabbits and with the
highest dose in rats. The effects on fetal mortality are
logicalconsequences of the alterations in hormonal levels brought about
by this drug. Therefore, thepossibility exists that spontaneous abortion
may occur if the drug is administered duringpregnancy.Leuprolide acetate
is contraindicated in children demonstrating hypersensitivity to
GnRH,GnRH agonist analogs, or any of the excipients.\
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LUPRON DEPOT-PED Package InsertPage 4 of 9A report of an anaphylactic
reaction to synthetic GnRH (Factrel) has been reported in themedical
literature.1WARNINGSDuring the early phase of therapy, gonadotropins and
sex steroids rise above baselinebecause of the natural stimulatory
effect of the drug. Therefore, an increase in clinical signsand symptoms
may be observed. (See CLINICAL PHARMACOLOGY section.)Noncompliance with
drug regimen or inadequate dosing may result in inadequate control ofthe
pubertal process. The consequences of poor control include the return of
pubertal signssuch as menses, breast development, and testicular growth.
The long-term consequences ofinadequate control of gonadal steroid
secretion are unknown, but may include a furthercompromise of adult
stature.PRECAUTIONSLaboratory Tests Response to LUPRON DEPOT-PED should
be monitored 1-2 months afterthe start of therapy with a GnRH
stimulation test and sex steroid levels. Measurement of boneage for
advancement should be done every 6-12 months.Sex steroids may increase
or rise above prepubertal levels if the dose is inadequate. (SeeWARNINGS
section.) Once a therapeutic dose has been established, gonadotropin and
sexsteroid levels will decline to prepubertal levels.Drug Interactions
No pharmacokinetic-based drug-drug interaction studies have
beenconducted. However, because leuprolide acetate is a peptide that is
primarily degraded bypeptidase and not by cytochrome P-450 enzymes as
noted in specific studies, and the drug isonly about 46% bound to plasma
proteins, drug interactions would not be expected to
occur.Drug/Laboratory Test Interactions Administration of LUPRON DEPOT
3.75 mg in womenresults in suppression of the pituitary-gonadal system.
Normal function is usually restoredwithin three months after treatment
is discontinued. Therefore, diagnostic tests of pituitarygonadotropic
and gonadal functions conducted during treatment and for up to three
monthsafter discontinuation of LUPRON DEPOT may be
misleading.Information for Parents Prior to starting therapy with LUPRON
DEPOT-PED, the parent orguardian must be aware of the importance of
continuous therapy. Adherence to 4 week drugadministration schedules
must be accepted if therapy is to be successful.• During the first 2
months of therapy, a female may experience menses or spotting.
Ifbleeding continues beyond the second month, notify the physician.• Any
irritation at the injection site should be reported to the physician
immediately.• Report any unusual signs or symptoms to the
physician.Carcinogenesis, Mutagenesis, Impairment of Fertility A
two-year carcinogenicity studywas conducted in rats and mice. In rats, a
dose-related increase of benign pituitary hyperplasiaand benign
pituitary adenomas was noted at 24 months when the drug was
administeredsubcutaneously at high daily doses (0.6 to 4 mg/kg). There
was a significant but not dose-\
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LUPRON DEPOT-PED Package InsertPage 5 of 9related increase of pancreatic
islet-cell adenomas in females and of testicular interstitial
celladenomas in males (highest incidence in the low dose group). In
mice, no leuprolide acetate-induced tumors or pituitary abnormalities
were observed at a dose as high as 60 mg/kg for twoyears. Adult patients
have been treated with leuprolide acetate for up to three years with
dosesas high as 10 mg/day and for two years with doses as high as 20
mg/day withoutdemonstrable pituitary abnormalities.Although no clinical
studies have been completed in children to assess the full
reversibilityof fertility suppression, animal studies (prepubertal and
adult rats and monkeys) with leuprolideacetate and other GnRH analogs
have shown functional recovery. However, following a studywith
leuprolide acetate, immature male rats demonstrated tubular degeneration
in the testeseven after a recovery period. In spite of the failure to
recover histologically, the treated malesproved to be as fertile as the
controls. Also, no histologic changes were observed in the femalerats
following the same protocol. In both sexes, the offspring of the treated
animals appearednormal. The effect of the treatment of the parents on
the reproductive performance of the F1generation was not tested. The
clinical significance of these findings is unknown.Pregnancy,
Teratogenic Effects Pregnancy Category X. (See
CONTRAINDICATIONSsection.)Nursing Mothers It is not known whether
leuprolide acetate is excreted in human milk.LUPRON should not be used
by nursing mothers.Geriatric Use See also the labeling for LUPRON DEPOT
7.5 mg which is indicated for thepalliative treatment of advanced
prostate cancer. For LUPRON DEPOT-PED 11.25 mg andLUPRON DEPOT-PED 15
mg, no clinical information has been established for persons aged65 and
over.ADVERSE REACTIONSClinical TrialsPotential exacerbation of signs and
symptoms during the first few weeks of treatment (SeePRECAUTIONS
section.) is a concern in patients with rapidly advancing central
precociouspuberty.In two studies of children with central precocious
puberty, in 2% or more of the patientsreceiving the drug, the following
adverse reactions were reported to have a possible orprobable
relationship to drug as ascribed by the treating physician. Reactions
which are notconsidered drug-related are excluded.\
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LUPRON DEPOT-PED Package InsertPage 6 of 9Number of PatientsN =
395(%)Body as a WholeGeneral Pain7(2)Integumentary
SystemAcne/Seborrhea7(2)Injection Site Reactions Including
Abscess21(5)Rash Including Erythema Multiforme8(2)Urogenital
SystemVaginitis/Bleeding/Discharge7(2)In those same studies, the
following adverse reactions were reported in less than 2% of
thepatients.Body as a Whole - Body Odor, Fever, Headache, Infection;
Cardiovascular System - Syncope,Vasodilation; Digestive System -
Dysphagia, Gingivitis, Nausea/Vomiting; Endocrine System -Accelerated
Sexual Maturity; Metabolic and Nutritional Disorders - Peripheral Edema,
WeightGain; Nervous System - Emotional Lability, Nervousness,
Personality Disorder, Somnolence;Respiratory System - Epistaxis;
Integumentary System - Alopecia, Skin Striae; UrogenitalSystem - Cervix
Disorder, Gynecomastia/Breast Disorders, Urinary
Incontinence.PostmarketingDuring postmarketing surveillance, which
includes other dosage forms, the following adverseevents were
reported.Symptoms consistent with an anaphylactoid or asthmatic process
have been rarelyreported. Rash, urticaria, and photosensitivity
reactions have also been reported.Localized reactions including
induration and abscess have been reported at the site
ofinjection.Cardiovascular System - Hypotension; Hemic and Lymphatic
System - Decreased WBC;Central/Peripheral Nervous System - Peripheral
neuropathy, Spinal fracture/paralysis;Musculoskeletal System -
Tenosynovitis-like symptoms; Urogenital System - Prostate pain.See other
LUPRON DEPOT and LUPRON Injection package inserts for other
eventsreported in different patient populations.OVERDOSAGEIn rats,
subcutaneous administration of 125 to 250 times the recommended human
pediatricdose, expressed on a per body weight basis, resulted in
dyspnea, decreased activity, and localirritation at the injection site.
There is no evidence at present that there is a clinical counterpartof
this phenomenon. In early clinical trials using leuprolide acetate in
adult patients, doses ashigh as 20 mg/day for up to two years caused no
adverse effects differing from those observedwith the 1 mg/day
dose.DOSAGE AND ADMINISTRATIONLUPRON DEPOT-PED must be administered
under the supervision of a physician.\
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Page 7\
LUPRON DEPOT-PED Package InsertPage 7 of 9The dose of LUPRON DEPOT-PED
must be individualized for each child. The dose isbased on a mg/kg ratio
of drug to body weight. Younger children require higher doses ona mg/kg
ratio.For each dosage form, after 1-2 months of initiating therapy or
changing doses, the childmust be monitored with a GnRH stimulation test,
sex steroids, and Tanner staging to confirmdownregulation. Measurements
of bone age for advancement should be monitored every 6-12months. The
dose should be titrated upward until no progression of the condition is
notedeither clinically and/or by laboratory parameters.The first dose
found to result in adequate downregulation can probably be maintained
forthe duration of therapy in most children. However, there are
insufficient data to guide dosageadjustment as patients move into higher
weight categories after beginning therapy at veryyoung ages and low
dosages. It is recommended that adequate downregulation be verified
insuch patients whose weight has increased significantly while on
therapy.Discontinuation of LUPRON DEPOT-PED should be considered before
age 11 for femalesand age 12 for males.The recommended starting dose is
0.3 mg/kg/4 weeks (minimum 7.5 mg) administered asa single intramuscular
injection. The starting dose will be dictated by the child's
weight.&#8804; 25 kg7.5 mg\> 25-37.5 kg11.25 mg\> 37.5 kg15 mgIf total
downregulation is not achieved, the dose should be titrated upward in
increments of3.75 mg every 4 weeks. This dose will be considered the
maintenance dose.The lyophilized microspheres are to be reconstituted
and administered as a singleintramuscular injection. For optimal
performance of the prefilled dual chamber syringe (PDS),read and follow
the following instructions:1. The LUPRON DEPOT powder should be visually
inspected and the syringe should NOTBE USED if clumping or caking is
evident. A thin layer of powder on the wall of thesyringe is considered
normal. The diluent should appear clear.2. To prepare for injection,
screw the white plunger into the end stopper until the stopperbegins to
turn.3. Hold the syringe UPRIGHT. Release the diluent by SLOWLY PUSHING
(6 to 8 seconds)the plunger until the first stopper is at the blue line
in the middle of the barrel.4. Keep the syringe UPRIGHT. Gently mix the
microspheres (powder) thoroughly to form auniform suspension. The
suspension will appear milky. If the powder adheres to thestopper or
caking/clumping is present, tap the syringe with your finger to
disperse. DONOT USE if any of the powder has not gone into suspension.\
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Page 8\
LUPRON DEPOT-PED Package InsertPage 8 of 95. Hold the syringe UPRIGHT.
With the opposite hand pull the needle cap upward withouttwisting.6.
Keep the syringe UPRIGHT. Advance the plunger to expel the air from the
syringe.7. Inject the entire contents of the syringe intramuscularly at
the time of reconstitution. Thesuspension settles very quickly following
reconstitution; therefore, LUPRON DEPOTshould be mixed and used
immediately.NOTE: Aspirated blood would be visible just below the luer
lock connection if a blood vesselis accidentally penetrated. If present,
blood can be seen through the transparent LuproLoc™safety device.AFTER
INJECTION8. Withdraw the needle. Immediately activate the LuproLoc™
safety device by pushing thearrow forward with the thumb or finger until
the device is fully extended and a CLICK isheard or felt.Since the
product does not contain a preservative, the suspension should be
discarded ifnot used immediately.As with other drugs administered by
injection, the injection site should be variedperiodically.HOW
SUPPLIEDLUPRON DEPOT-PED is packaged as follows:Kit with prefilled
dual-chamber syringe7.5 mgNDC 0300-2108-01Kit with prefilled
dual-chamber syringe11.25 mgNDC 0300-2282-01Kit with prefilled
dual-chamber syringe15 mgNDC 0300-2440-01Each syringe contains sterile
lyophilized microspheres which is leuprolide incorporated in
abiodegradable copolymer of lactic and glycolic acids. When mixed with
diluent,LUPRON DEPOT-PED is administered as a single IM injection.An
information pamphlet for parents is included with the kit.Store at 25°C
(77°F); excursions permitted to 15-30°C (59-86°F) \[See USP
ControlledRoom Temperature\]REFERENCE1. MacLeod TL, et al. Anaphylactic
reaction to synthetic luteinizing hormone-releasinghormone. Fertil
Steril 1987 Sept; 48(3):500-502.U.S. Patent Nos. 4,652,441; 4,677,191;
4,728,721; 4,849,228; 4,917,893; 5,330,767;5,476,663; 5,823,997;
5,980,488; and 6,036,976. Other patents pending.\
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Page 9\
LUPRON DEPOT-PED Package InsertPage 9 of 9Manufactured forTAP
Pharmaceuticals Inc.Lake Forest, IL 60045, U.S.A.by Takeda
Pharmaceutical Company LimitedOsaka, JAPAN 540-8645TM-Trademark® ---
Registered Trademark(Nos. 2108, 2282, 2440)03-5411-R13; Revised:
January, 2005© 1993 -- 2005, TAP Pharmaceutical Products Inc.

EXHIBIT IX.

LUPRON DEPOT 3.75 PACKAGE INSERT

LUPRON DEPOT 3.75 mg Package InsertPage 1 of 18This is combined
labeling. Examples of different fonts and colors appear below.• General
information• Information on endometriosis• Information on uterine
fibroidsLUPRON DEPOT®3.75 mg(leuprolide acetate for depot
suspension)DESCRIPTIONLeuprolide acetate is a synthetic nonapeptide
analog of naturally occurringgonadotropin-releasing hormone (GnRH or
LH-RH). The analog possesses greaterpotency than the natural hormone.
The chemical name is
5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide
acetate(salt) with the following structural formula:LUPRON DEPOT is
available in a prefilled dual-chamber syringe containing
sterilelyophilized microspheres which, when mixed with diluent, become a
suspensionintended as a monthly intramuscular injection.The front
chamber of LUPRON DEPOT 3.75 mg prefilled dual-chamber syringecontains
leuprolide acetate (3.75 mg), purified gelatin (0.65 mg), DL-lactic and
glycolicacids copolymer (33.1 mg), and D-mannitol (6.6 mg). The second
chamber of diluentcontains carboxymethylcellulose sodium (5 mg),
D-mannitol (50 mg),polysorbate 80 (1 mg), water for injection, USP, and
glacial acetic acid, USP to controlpH.During the manufacture of LUPRON
DEPOT 3.75 mg, acetic acid is lost, leaving thepeptide.CLINICAL
PHARMACOLOGYLeuprolide acetate is a long-acting GnRH analog. A single
monthly injection ofLUPRON DEPOT 3.75 mg results in an initial
stimulation followed by a prolongedsuppression of pituitary
gonadotropins. Repeated dosing at monthly intervals results indecreased
secretion of gonadal steroids; consequently, tissues and functions
thatdepend on gonadal steroids for their maintenance become quiescent.
This effect isreversible on discontinuation of drug therapy.Leuprolide
acetate is not active when given orally. Intramuscular injection of
thedepot formulation provides plasma concentrations of leuprolide over a
period of onemonth.\
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LUPRON DEPOT 3.75 mg Package InsertPage 2 of
18PharmacokineticsAbsorption A single dose of LUPRON DEPOT 3.75 mg was
administered byintramuscular injection to healthy female volunteers. The
absorption of leuprolide wascharacterized by an initial increase in
plasma concentration, with peak concentrationranging from 4.6 to 10.2
ng/mL at four hours postdosing. However, intact leuprolide andan
inactive metabolite could not be distinguished by the assay used in the
study.Following the initial rise, leuprolide concentrations started to
plateau within two daysafter dosing and remained relatively stable for
about four to five weeks with plasmaconcentrations of about 0.30
ng/mL.Distribution The mean steady-state volume of distribution of
leuprolide followingintravenous bolus administration to healthy male
volunteers was 27 L. In vitro bindingto human plasma proteins ranged
from 43% to 49%.Metabolism In healthy male volunteers, a 1 mg bolus of
leuprolide administeredintravenously revealed that the mean systemic
clearance was 7.6 L/h, with a terminalelimination half-life of
approximately 3 hours based on a two compartment model.In rats and dogs,
administration of14C-labeled leuprolide was shown to bemetabolized to
smaller inactive peptides, a pentapeptide (Metabolite I),
tripeptides(Metabolites II and III) and a dipeptide (Metabolite IV).
These fragments may be furthercatabolized.The major metabolite (M-I)
plasma concentrations measured in 5 prostate cancerpatients reached
maximum concentration 2 to 6 hours after dosing and wereapproximately 6%
of the peak parent drug concentration. One week after dosing, meanplasma
M-I concentrations were approximately 20% of mean leuprolide
concentrations.Excretion Following administration of LUPRON DEPOT 3.75
mg to 3 patients, lessthan 5% of the dose was recovered as parent and
M-I metabolite in the urine.Special Populations The pharmacokinetics of
the drug in hepatically and renallyimpaired patients have not been
determined.Drug Interactions No pharmacokinetic-based drug-drug
interaction studies have beenconducted with LUPRON DEPOT. However,
because leuprolide acetate is a peptidethat is primarily degraded by
peptidase and not by cytochrome P-450 enzymes as notedin specific
studies, and the drug is only about 46% bound to plasma proteins,
druginteractions would not be expected to occur.CLINICAL
STUDIESEndometriosis: In controlled clinical studies, LUPRON DEPOT 3.75
mg monthly for sixmonths was shown to be comparable to danazol 800
mg/day in relieving the clinicalsign/symptoms of endometriosis (pelvic
pain, dysmenorrhea, dyspareunia, pelvic tenderness, andinduration) and
in reducing the size of endometrial implants as evidenced by
laparoscopy. Theclinical significance of a decrease in endometriotic
lesions is not known at this time, and inaddition laparoscopic staging
of endometriosis does not necessarily correlate with the severity
ofsymptoms.LUPRON DEPOT 3.75 mg monthly induced amenorrhea in 74% and
98% of the patientsafter the first and second treatment months
respectively. Most of the remaining patients reportedepisodes of only
light bleeding or spotting. In the first, second and third
post-treatment months,\
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LUPRON DEPOT 3.75 mg Package InsertPage 3 of 18normal menstrual cycles
resumed in 7%, 71% and 95% of patients, respectively, excluding thosewho
became pregnant.Figure 1 illustrates the percent of patients with
symptoms at baseline, final treatment visitand sustained relief at 6 and
12 months following discontinuation of treatment for the varioussymptoms
evaluated during two controlled clinical studies. This included all
patients at end oftreatment and those who elected to participate in the
follow-up period. This might provide aslight bias in the results at
follow-up as 75% of the original patients entered the follow-up
study,and 36% were evaluated at 6 months and 26% at 12 months.Hormonal
replacement therapy: Two clinical studies with a treatment duration of
12 monthsindicate that concurrent hormonal therapy (norethindrone
acetate 5 mg daily) is effective insignificantly reducing the loss of
bone mineral density associated with LUPRON, withoutcompromising the
efficacy of LUPRON in relieving symptoms of endometriosis. (All patients
inthese studies received calcium supplementation with 1000 mg elemental
calcium). Onecontrolled, randomized and double-blind study included 51
women treated withLUPRON DEPOT alone and 55 women treated with LUPRON
plus norethindrone acetate 5 mgdaily. The second study was an open label
study in which 136 women were treated withLUPRON plus norethindrone
acetate 5 mg daily. This study confirmed the reduction in loss ofbone
mineral density that was observed in the controlled study. Suppression
of menses wasmaintained throughout treatment in 84% and 73% of patients
receiving LD/N in the controlled\
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LUPRON DEPOT 3.75 mg Package InsertPage 4 of 18study and open label
study, respectively. The median time for menses resumption after
treatmentwith LD/N was 8 weeks.Figure 2 illustrates the mean pain scores
for the LD/N group from the controlled study.BaselineTreatment
AverageFigure 2Treatment Period Mean Pain Scores For LD/N\*
PatientsDysmenorrheaPelvic PainDeep DyspareuniaPelvic TendernessPelvic
Induration4 = Severe3 = Moderate2 = Mild1 = None\* LD/N = LUPRON DEPOT
3.75 mg plus norethindrone acetate 5 mg dailyUterine Leiomyomata
(Fibroids): In controlled clinical trials, administration of LUPRON
DEPOT 3.75 mg fora period of three or six months was shown to decrease
uterine and fibroid volume, thus allowing for relief ofclinical symptoms
(abdominal bloating, pelvic pain, and pressure). Excessive vaginal
bleeding(menorrhagia and menometrorrhagia) decreased, resulting in
improvement in hematologic parameters.In three clinical trials,
enrollment was not based on hematologic status. Mean uterine
volumedecreased by 41% and myoma volume decreased by 37% at final visit
as evidenced by ultrasound or MRI.These patients also experienced a
decrease in symptoms including excessive vaginal bleeding and
pelvicdiscomfort. Benefit occurred by three months of therapy, but
additional gain was observed with anadditional three months of LUPRON
DEPOT 3.75 mg. Ninety-five percent of these patients becameamenorrheic
with 61%, 25%, and 4% experiencing amenorrhea during the first, second,
and third treatmentmonths respectively.Post-treatment follow-up was
carried out for a small percentage of LUPRON DEPOT 3.75 mg patientsamong
the 77% who demonstrated a &#8805; 25% decrease in uterine volume while
on therapy. Menses usuallyreturned within two months of cessation of
therapy. Mean time to return to pretreatment uterine size was8.3 months.
Regrowth did not appear to be related to pretreatment uterine volume.In
another controlled clinical study, enrollment was based on hematocrit
&#8804; 30% and/or hemoglobin&#8804; 10.2 g/dL. Administration of LUPRON
DEPOT 3.75 mg, concomitantly with iron, produced an increase of&#8805;
6% hematocrit and &#8805; 2 g/dL hemoglobin in 77% of patients at three
months of therapy. The meanchange in hematocrit was 10.1% and the mean
change in hemoglobin was 4.2 g/dL. Clinical response was\
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LUPRON DEPOT 3.75 mg Package InsertPage 5 of 18judged to be a hematocrit
of &#8805; 36% and hemoglobin of &#8805; 12 g/dL, thus allowing for
autologous blooddonation prior to surgery. At three months, 75% of
patients met this criterion.At three months, 80% of patients experienced
relief from either menorrhagia or menometrorrhagia. Aswith the previous
studies, episodes of spotting and menstrual-like bleeding were noted in
some patients.In this same study, a decrease of &#8805; 25% was seen in
uterine and myoma volumes in 60% and 54% ofpatients respectively. LUPRON
DEPOT 3.75 mg was found to relieve symptoms of bloating, pelvic pain,and
pressure.There is no evidence that pregnancy rates are enhanced or
adversely affected bythe use of LUPRON DEPOT 3.75 mg.INDICATIONS AND
USAGEEndometriosis:LUPRON DEPOT 3.75 mg is indicated for management of
endometriosis, including pain reliefand reduction of endometriotic
lesions. LUPRON DEPOT monthly with norethindrone acetate5 mg daily is
also indicated for initial management of endometriosis and for
management ofrecurrence of symptoms. (Refer also to norethindrone
acetate prescribing information forWARNINGS, PRECAUTIONS,
CONTRAINDICATIONS and ADVERSE REACTIONSassociated with norethindrone
acetate). Duration of initial treatment or retreatment should belimited
to 6 months.Uterine Leiomyomata (Fibroids):LUPRON DEPOT 3.75 mg
concomitantly with iron therapy is indicated for the preoperative
hematologicimprovement of patients with anemia caused by uterine
leiomyomata. The clinician may wish to consider aone-month trial period
on iron alone inasmuch as some of the patients will respond to iron
alone. (SeeTable 1.) LUPRON may be added if the response to iron alone
is considered inadequate. Recommendedduration of therapy with LUPRON
DEPOT 3.75 mg is up to three months.Experience with LUPRON DEPOT in
females has been limited to women 18 years of age and older.Table
1PERCENT OF PATIENTS ACHIEVINGHEMOGLOBIN &#8805; 12 GM/DLTreatment
GroupWeek 4Week 8Week 12LUPRON DEPOT 3.75 mg with Iron41\*71\*\*79\*Iron
Alone174056\* P-Value \< 0.01\*\* P-Value \< 0.001CONTRAINDICATIONS1.
Hypersensitivity to GnRH, GnRH agonist analogs or any of the excipients
inLUPRON DEPOT.2. Undiagnosed abnormal vaginal bleeding.3. LUPRON DEPOT
is contraindicated in women who are or may become pregnantwhile
receiving the drug. LUPRON DEPOT may cause fetal harm whenadministered
to a pregnant woman. Major fetal abnormalities were observed inrabbits
but not in rats after administration of LUPRON DEPOT throughout
gestation.There was increased fetal mortality and decreased fetal
weights in rats and rabbits.\
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LUPRON DEPOT 3.75 mg Package InsertPage 6 of 18(See Pregnancy section.)
The effects on fetal mortality are expected consequencesof the
alterations in hormonal levels brought about by the drug. If this drug
is usedduring pregnancy, or if the patient becomes pregnant while taking
this drug, thepatient should be apprised of the potential hazard to the
fetus.4. Use in women who are breast-feeding. (See Nursing Mothers
section.)5. Norethindrone acetate is contraindicated in women with the
following conditions:&#8722; Thrombophlebitis, thromboembolic disorders,
cerebral apoplexy, or a past historyof these conditions&#8722; Markedly
impaired liver function or liver disease&#8722; Known or suspected
carcinoma of the breastWARNINGSSafe use of leuprolide acetate or
norethindrone acetate in pregnancy has not beenestablished clinically.
Before starting treatment with LUPRON DEPOT, pregnancy mustbe
excluded.When used monthly at the recommended dose, LUPRON DEPOT usually
inhibitsovulation and stops menstruation. Contraception is not insured,
however, by takingLUPRON DEPOT. Therefore, patients should use
non-hormonal methods ofcontraception. Patients should be advised to see
their physician if they believe theymay be pregnant. If a patient
becomes pregnant during treatment, the drug must bediscontinued and the
patient must be apprised of the potential risk to the fetus.During the
early phase of therapy, sex steroids temporarily rise above
baselinebecause of the physiologic effect of the drug. Therefore, an
increase in clinical signsand symptoms may be observed during the
initial days of therapy, but these willdissipate with continued
therapy.Symptoms consistent with an anaphylactoid or asthmatic process
have been rarelyreported post-marketing.The following applies to
co-treatment with LUPRON and norethindrone acetate:Norethindrone acetate
treatment should be discontinued if there is a sudden partialor complete
loss of vision or if there is sudden onset of proptosis, diplopia, or
migraine.If examination reveals papilledema or retinal vascular lesions,
medication should bewithdrawn.Because of the occasional occurrence of
thrombophlebitis and pulmonary embolismin patients taking progestogens,
the physician should be alert to the earliestmanifestations of the
disease in women taking norethindrone acetate.Assessment and management
of risk factors for cardiovascular disease isrecommended prior to
initiation of add-back therapy with norethindrone acetate.Norethindrone
acetate should be used with caution in women with risk factors,
includinglipid abnormalities or cigarette smoking.PRECAUTIONSInformation
for Patients An information pamphlet for patients is included with
theproduct. Patients should be aware of the following information:1.
Since menstruation usually stops with effective doses of LUPRON DEPOT,
thepatient should notify her physician if regular menstruation persists.
Patients\
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Page 7\
LUPRON DEPOT 3.75 mg Package InsertPage 7 of 18missing successive doses
of LUPRON DEPOT may experience breakthroughbleeding.2. Patients should
not use LUPRON DEPOT if they are pregnant, breast feeding,have
undiagnosed abnormal vaginal bleeding, or are allergic to any of
theingredients in LUPRON DEPOT.3. Safe use of the drug in pregnancy has
not been established clinically. Therefore, anon-hormonal method of
contraception should be used during treatment. Patientsshould be advised
that if they miss successive doses of LUPRON DEPOT,breakthrough bleeding
or ovulation may occur with the potential for conception. If apatient
becomes pregnant during treatment, she should discontinue treatment
andconsult her physician.4. Adverse events occurring in clinical studies
with LUPRON DEPOT that areassociated with hypoestrogenism include: hot
flashes, headaches, emotionallability, decreased libido, acne, myalgia,
reduction in breast size, and vaginaldryness. Estrogen levels returned
to normal after treatment was discontinued.5. Patients should be
counseled on the possibility of the development or worsening
ofdepression and the occurrence of memory disorders.6. The induced
hypoestrogenic state also results in a loss in bone density over
thecourse of treatment, some of which may not be reversible. For a
period up to sixmonths, this bone loss should not be clinically
significant. Clinical studies showthat concurrent hormonal therapy with
norethindrone acetate 5 mg daily is effectivein reducing loss of bone
mineral density that occurs with LUPRON. (All patientsreceived calcium
supplementation with 1000 mg elemental calcium.) (SeeChanges in Bone
Density section).7. If the symptoms of endometriosis recur after a
course of therapy, retreatment with asix-month course of LUPRON DEPOT
and norethindrone acetate 5 mg daily maybe considered. Retreatment
beyond this one six month course cannot berecommended. It is recommended
that bone density be assessed beforeretreatment begins to ensure that
values are within normal limits. Retreatment withLUPRON DEPOT alone is
not recommended.8. In patients with major risk factors for decreased
bone mineral content such aschronic alcohol and/or tobacco use, strong
family history of osteoporosis, or chronicuse of drugs that can reduce
bone mass such as anticonvulsants or corticosteroids,LUPRON DEPOT
therapy may pose an additional risk. In these patients, the risksand
benefits must be weighed carefully before therapy with LUPRON DEPOT
aloneis instituted, and concomitant treatment with norethindrone acetate
5 mg dailyshould be considered. Retreatment with gonadotropin-releasing
hormone analogs,including LUPRON is not advisable in patients with major
risk factors for loss ofbone mineral content.9. Because norethindrone
acetate may cause some degree of fluid retention,conditions which might
be influenced by this factor, such as epilepsy, migraine,asthma, cardiac
or renal dysfunctions require careful observation duringnorethindrone
acetate add-back therapy.10. Patients who have a history of depression
should be carefully observed duringtreatment with norethindrone acetate
and norethindrone acetate should bediscontinued if severe depression
occurs.\
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LUPRON DEPOT 3.75 mg Package InsertPage 8 of 18Laboratory Tests See
ADVERSE REACTIONS section.Drug Interactions See CLINICAL PHARMACOLOGY,
Pharmacokinetics.Drug/Laboratory Test Interactions Administration of
LUPRON DEPOT in therapeuticdoses results in suppression of the
pituitary-gonadal system. Normal function is usuallyrestored within
three months after treatment is discontinued. Therefore, diagnostic
testsof pituitary gonadotropic and gonadal functions conducted during
treatment and for upto three months after discontinuation of LUPRON
DEPOT may be misleading.Carcinogenesis, Mutagenesis, Impairment of
Fertility A two-year carcinogenicitystudy was conducted in rats and
mice. In rats, a dose-related increase of benignpituitary hyperplasia
and benign pituitary adenomas was noted at 24 months when thedrug was
administered subcutaneously at high daily doses (0.6 to 4 mg/kg). There
wasa significant but not dose-related increase of pancreatic islet-cell
adenomas in femalesand of testicular interstitial cell adenomas in males
(highest incidence in the low dosegroup). In mice, no leuprolide
acetate-induced tumors or pituitary abnormalities wereobserved at a dose
as high as 60 mg/kg for two years. Patients have been treated
withleuprolide acetate for up to three years with doses as high as 10
mg/day and for twoyears with doses as high as 20 mg/day without
demonstrable pituitary abnormalities.Mutagenicity studies have been
performed with leuprolide acetate using bacterialand mammalian systems.
These studies provided no evidence of a mutagenicpotential.Clinical and
pharmacologic studies in adults (\>18 years) with leuprolide acetate
andsimilar analogs have shown reversibility of fertility suppression
when the drug isdiscontinued after continuous administration for periods
of up to 24 weeks. Although noclinical studies have been completed in
children to assess the full reversibility of fertilitysuppression,
animal studies (prepubertal and adult rats and monkeys) with
leuprolideacetate and other GnRH analogs have shown functional
recovery.Pregnancy, Teratogenic Effects Pregnancy Category X.
(SeeCONTRAINDICATIONS section.) When administered on day 6 of pregnancy
at testdosages of 0.00024, 0.0024, and 0.024 mg/kg (1/300 to 1/3 of the
human dose) torabbits, LUPRON DEPOT produced a dose-related increase in
major fetalabnormalities. Similar studies in rats failed to demonstrate
an increase in fetalmalformations. There was increased fetal mortality
and decreased fetal weights withthe two higher doses of LUPRON DEPOT in
rabbits and with the highest dose(0.024 mg/kg) in rats.Nursing Mothers
It is not known whether LUPRON DEPOT is excreted in human milk.Because
many drugs are excreted in human milk, and because the effects ofLUPRON
DEPOT on lactation and/or the breast-fed child have not been
determined,LUPRON DEPOT should not be used by nursing mothers.Pediatric
Use Experience with LUPRON DEPOT 3.75 mg for treatment ofendometriosis
has been limited to women 18 years of age and older. See\
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Page 9\
LUPRON DEPOT 3.75 mg Package InsertPage 9 of 18LUPRON
DEPOT-PED®(leuprolide acetate for depot suspension) labeling for the
safetyand effectiveness in children with central precocious
puberty.Geriatric Use This product has not been studied in women over 65
years of age and isnot indicated in this population.ADVERSE
REACTIONSClinical TrialsEstradiol levels may increase during the first
weeks following the initial injection ofLUPRON, but then decline to
menopausal levels. This transient increase in estradiolcan be associated
with a temporary worsening of signs and symptoms. (SeeWARNINGS
section.)As would be expected with a drug that lowers serum estradiol
levels, the mostfrequently reported adverse reactions were those related
to hypoestrogenism.The monthly formulation of LUPRON DEPOT 3.75 mg was
utilized incontrolled clinical trials that studied the drug in 166
endometriosis and 166 uterinefibroids patients. Adverse events reported
in &#8805;5% of patients in either of thesepopulations and thought to be
potentially related to drug are noted in the following table.\
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LUPRON DEPOT 3.75 mg Package InsertPage 10 of 18Table 2ADVERSE EVENTS
REPORTED TO BE CAUSALLY RELATED TODRUG IN &#8805; 5% OF
PATIENTSEndometriosis (2 Studies)Uterine Fibroids (4
Studies)LUPRONDEPOT3.75 mgDanazolPlaceboLUPRONDEPOT3.75
mgPlaceboN=166N=136N=31N=166N=163N(%)N(%)N(%)N(%)N(%)Body as a
WholeAsthenia5(3)9(7)0(0)14(8.4)8(4.9)General
pain31(19)22(16)1(3)14(8.4)10(6.1)Headache\*53(32)30(22)2(6)43
(25.9)29(17.8)Cardiovascular SystemHot
flashes/sweats\*139(84)77(57)9(29)121 (72.9)29(17.8)Gastrointestinal
SystemNausea/vomiting21(13)17(13)1(3)8(4.8)6(3.7)GI
disturbances\*11(7)8(6)1(3)5(3.0)2(1.2)Metabolic and Nutritional
DisordersEdema12(7)17(13)1(3)9(5.4)2(1.2)Weight
gain/loss22(13)36(26)0(0)5(3.0)2(1.2)Endocrine
SystemAcne17(10)27(20)0(0)0(0)0(0)Hirsutism2(1)9(7)1(3)1(0.6)0(0)Musculoskeletal
SystemJoint
disorder\*14(8)11(8)0(0)13(7.8)5(3.1)Myalgia\*1(1)7(5)0(0)1(0.6)0(0)Nervous
SystemDecreased libido\*19(11)6(4)0(0)3(1.8)0(0)Depression/emotional
lability\*36(22)27(20)1(3)18
(10.8)7(4.3)Dizziness19(11)4(3)0(0)3(1.8)6(3.7)Nervousness\*8(5)11(8)0(0)8(4.8)1(0.6)Neuromuscular
disorders\*11(7)17(13)0(0)3(1.8)0(0)Paresthesias12(7)11(8)0(0)2(1.2)1(0.6)Skin
and AppendagesSkin reactions17(10)20(15)1(3)5(3.0)2(1.2)Urogenital
SystemBreast
changes/tenderness/pain\*10(6)12(9)0(0)3(1.8)7(4.3)Vaginitis\*46(28)23(17)0(0)19
(11.4)3(1.8)In these same studies, symptoms reported in \<5% of patients
included: Body as a Whole - Bodyodor, Flu syndrome, Injection site
reactions; Cardiovascular System - Palpitations, Syncope,Tachycardia;
Digestive System - Appetite changes, Dry mouth, Thirst; Endocrine System
-Androgen-like effects; Hemic and Lymphatic System - Ecchymosis,
Lymphadenopathy; NervousSystem -- Anxiety\*, Insomnia/Sleep disorders\*,
Delusions, Memory disorder, Personalitydisorder; Respiratory System -
Rhinitis; Skin and Appendages - Alopecia, Hair disorder, Naildisorder;
Special Senses - Conjunctivitis, Ophthalmologic disorders\*, Taste
perversion;Urogenital System - Dysuria\*, Lactation, Menstrual
disorders.\* = Possible effect of decreased estrogen.\
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LUPRON DEPOT 3.75 mg Package InsertPage 11 of 18In one controlled
clinical trial utilizing the monthly formulation of LUPRON DEPOT,
patients diagnosed withuterine fibroids received a higher dose (7.5 mg)
of LUPRON DEPOT. Events seen with this dose that were thoughtto be
potentially related to drug and were not seen at the lower dose included
glossitis, hypesthesia, lactation,pyelonephritis, and urinary disorders.
Generally, a higher incidence of hypoestrogenic effects was observed at
thehigher dose.Table 3 lists the potentially drug-related adverse events
observed in at least 5% of patients in anytreatment group during the
first 6 months of treatment in the add-back clinical studies.In the
controlled clinical trial, 50 of 51 (98%) patients in the LD group and
48 of 55 (87%)patients in the LD/N group reported experiencing hot
flashes on one or more occasions duringtreatment. During Month 6 of
treatment, 32 of 37 (86%) patients in the LD group and 22 of 38(58%)
patients in the LD/N group reported having experienced hot flashes. The
mean number ofdays on which hot flashes were reported during this month
of treatment was 19 and 7 in the LDand LD/N treatment groups,
respectively. The mean maximum number of hot flashes in a dayduring this
month of treatment was 5.8 and 1.9 in the LD and LD/N treatment
groups,respectively.\
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Page 12\
LUPRON DEPOT 3.75 mg Package InsertPage 12 of 18Table 3TREATMENT-RELATED
ADVERSE EVENTS OCCURRING IN \>5% OF PATIENTSControlled StudyOpen Label
StudyLD - Only1N=51LD/N2N=55LD/N2N=136Adverse EventsN(%)N (%)N (%)Any
Adverse Event50(98)53 (96)126 (93)Body as a WholeAsthenia9(18)10 (18)15
(11)Headache/Migraine33(65)28 (51)63 (46)Injection Site
Reaction1(2)5(9)4(3)Pain12(24)16 (29)29 (21)Cardiovascular SystemHot
flashes/sweats50(98)48 (87)78 (57)Digestive SystemAltered Bowel
Function7(14)8 (15)14 (10)Changes in Appetite2(4)0(0)8(6)GI
Disturbance2(4)4(7)6(4)Nausea/Vomiting13(25)16 (29)17 (13)Metabolic and
Nutritional DisordersEdema0(0)5(9)9(7)Weight Changes6(12)7
(13)6(4)Nervous SystemAnxiety3(6)0(0)11(8)Depression/Emotional
Lability16(31)15 (27)46 (34)Dizziness/Vertigo8(16)6
(11)10(7)Insomnia/Sleep Disorder16(31)7 (13)20 (15)Libido
Changes5(10)2(4)10(7)Memory Disorder3(6)1(2)6(4)Nervousness4(8)2(4)15
(11)Neuromuscular Disorder1(2)5(9)4(3)Skin and
AppendagesAlopecia0(0)5(9)4(3)Androgen-Like Effects2(4)3(5)24
(18)Skin/Mucous Membrane Reaction2(4)5(9)15 (11)Urogenital SystemBreast
Changes/Pain/Tenderness3(6)7 (13)11(8)Menstrual
Disorders1(2)0(0)7(5)Vaginitis10(20)8 (15)11(8)1LD-Only = LUPRON DEPOT
3.75 mg2LD/N = LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg\
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Page 13\
LUPRON DEPOT 3.75 mg Package InsertPage 13 of 18Changes in Bone
DensityIn controlled clinical studies, patients with endometriosis (six
months of therapy) oruterine fibroids (three months of therapy) were
treated with LUPRON DEPOT 3.75 mg.In endometriosis patients, vertebral
bone density as measured by dual energy x-rayabsorptiometry (DEXA)
decreased by an average of 3.2% at six months compared withthe
pretreatment value. Clinical studies demonstrate that concurrent
hormonal therapy(norethindrone acetate 5 mg daily) and calcium
supplementation is effective insignificantly reducing the loss of bone
mineral density that occurs with LUPRONtreatment, without compromising
the efficacy of LUPRON in relieving symptoms ofendometriosis.LUPRON
DEPOT 3.75 mg plus norethindrone acetate 5 mg daily was evaluated intwo
clinical trials. The results from this regimen were similar in both
studies.LUPRON DEPOT 3.75 mg was used as a control group in one study.
The bone mineraldensity data of the lumbar spine from these two studies
are presented in Table 4.Table 4MEAN PERCENT CHANGE FROM BASELINE IN
BONEMINERAL DENSITY OF LUMBAR SPINE1Includes on-treatment measurements
that fell within 2-252 days after the first day of treatment.2Includes
on-treatment measurements \>252 days after the first day of
treatment.When LUPRON DEPOT 3.75 mg was administered for three months in
uterine fibroidpatients, vertebral trabecular bone mineral density as
assessed by quantitative digitalradiography (QDR) revealed a mean
decrease of 2.7% compared with baseline. Sixmonths after discontinuation
of therapy, a trend toward recovery was observed. Use ofLUPRON DEPOT for
longer than three months (uterine fibroids) or six months(endometriosis)
or in the presence of other known risk factors for decreased bonemineral
content may cause additional bone loss and is not recommended.LUPRON
DEPOT3.75mgLUPRON DEPOT 3.75 mg plusnorethindrone acetate 5 mg
dailyControlled StudyControlled StudyOpen Label
StudyNChangeNChangeNChangeWeek 24141-3.2%42-0.3%115-0.2%Week
52229-6.3%32-1.0%84-1.1%\
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Page 14\
LUPRON DEPOT 3.75 mg Package InsertPage 14 of 18Changes in Laboratory
Values During TreatmentPlasma EnzymesEndometriosis: During early
clinical trials with LUPRON DEPOT 3.75 mg, regular laboratorymonitoring
revealed that AST levels were more than twice the upper limit of normal
in only onepatient. There was no clinical or other laboratory evidence
of abnormal liver function.In two other clinical trials, 6 of 191
patients receiving LUPRON DEPOT 3.75 mg plusnorethindrone acetate 5 mg
daily for up to 12 months developed an elevated (at least twice theupper
limit of normal) SGPT or GGT. Five of the 6 increases were observed
beyond 6 months oftreatment. None were associated with elevated
bilirubin concentration.Uterine Leiomyomata (Fibroids): In clinical
trials with LUPRON DEPOT 3.75 mg, five (3%) patients had apost-treatment
transaminase value that was at least twice the baseline value and above
the upper limit ofthe normal range. None of the laboratory increases
were associated with clinical symptoms.LipidsEndometriosis: In earlier
clinical studies, 4% of the LUPRON DEPOT 3.75 mg patients and 1%of the
danazol patients had total cholesterol values above the normal range at
enrollment. Thesepatients also had cholesterol values above the normal
range at the end of treatment.Of those patients whose pretreatment
cholesterol values were in the normal range, 7% of theLUPRON DEPOT 3.75
mg patients and 9% of the danazol patients had post-treatment
valuesabove the normal range.The mean (±SEM) pretreatment values for
total cholesterol from all patients were 178.8(2.9) mg/dL in the LUPRON
DEPOT 3.75 mg groups and 175.3 (3.0) mg/dL in the danazolgroup. At the
end of treatment, the mean values for total cholesterol from all
patients were193.3 mg/dL in the LUPRON DEPOT 3.75 mg group and 194.4
mg/dL in the danazol group.These increases from the pretreatment values
were statistically significant (p\<0.03) in bothgroups.Triglycerides
were increased above the upper limit of normal in 12% of the patients
whoreceived LUPRON DEPOT 3.75 mg and in 6% of the patients who received
danazol.At the end of treatment, HDL cholesterol fractions decreased
below the lower limit of thenormal range in 2% of the LUPRON DEPOT 3.75
mg patients compared with 54% of thosereceiving danazol. LDL cholesterol
fractions increased above the upper limit of the normalrange in 6% of
the patients receiving LUPRON DEPOT 3.75 mg compared with 23% of
thosereceiving danazol. There was no increase in the LDL/HDL ratio in
patients receivingLUPRON DEPOT 3.75 mg but there was approximately a
two-fold increase in the LDL/HDLratio in patients receiving danazol.In
two other clinical trials, LUPRON DEPOT 3.75 mg plus norethindrone
acetate 5 mg dailywas evaluated for 12 months of treatment. LUPRON DEPOT
3.75 mg was used as a controlgroup in one study. Percent changes from
baseline for serum lipids and percentages of patientswith serum lipid
values outside of the normal range in the two studies are summarized in
thetables below.\
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Page 15\
LUPRON DEPOT 3.75 mg Package InsertPage 15 of 18Table 5SERUM LIPIDS:
MEAN PERCENT CHANGES FROMBASELINE VALUES AT TREATMENT WEEK
24LUPRONLUPRON plus norethindrone acetate 5 mg dailyControlled Study
(n=39)Controlled Study (n=41)Open Label Study (n=117)BaselineValue\*Wk
24% ChangeBaselineValue\*Wk 24% ChangeBaselineValue\*Wk 24% ChangeTotal
Cholesterol170.59.2%179.30.2%181.22.8%HDL
Cholesterol52.47.4%51.8-18.8%51.0-14.6%LDL
Cholesterol96.610.9%101.514.1%109.113.1%LDL/HDL
Ratio2.0\*\*5.0%2.1\*\*43.4%2.3\*\*39.4%Triglycerides107.817.5%130.29.5%105.413.8%\*mg/dL\*\*ratioChanges
from baseline tended to be greater at Week 52. After treatment, mean
serum lipidlevels from patients with follow up data returned to
pretreatment values.Table 6PERCENTAGE OF PATIENTS WITH SERUM LIPIDVALUES
OUTSIDE OF THE NORMAL RANGE\*Includes all patients regardless of
baseline value.Low HDL-cholesterol (\<40 mg/dL) and elevated
LDL-cholesterol (\>160 mg/dL) are recognizedrisk factors for
cardiovascular disease. The long-term significance of the observed
treatment-related changes in serum lipids in women with endometriosis is
unknown. Therefore assessmentof cardiovascular risk factors should be
considered prior to initiation of concurrent treatmentwith LUPRON and
norethindrone acetate.Uterine Leiomyomata (Fibroids): In patients
receiving LUPRON DEPOT 3.75 mg, mean changes incholesterol (+11 mg/dL to
+29 mg/dL), LDL cholesterol (+8 mg/dL to +22 mg/dL), HDL cholesterol
(0to +6 mg/dL), and the LDL/HDL ratio (-0.1 to +0.5) were observed
across studies. In the one study in whichtriglycerides were determined,
the mean increase from baseline was 32 mg/dL.Other ChangesEndometriosis:
The following changes were seen in approximately 5% to 8% of patients.
In theearlier comparative studies, LUPRON DEPOT 3.75 mg was associated
with elevations of LDHand phosphorus, and decreases in WBC counts.
Danazol therapy was associated with increasesLUPRONLUPRON plus
norethindrone acetate 5 mg dailyControlled Study(n=39)Controlled
Study(n=41)Open Label Study(n=117)Wk 0Wk 24\*Wk 0Wk 24\*Wk 0Wk 24\*Total
Cholesterol (\>240 mg/dL)15%23%15%20%6%7%HDL Cholesterol (\<40
mg/dL)15%10%15%44%15%41%LDL Cholesterol (\>160
mg/dL)0%8%5%7%9%11%LDL/HDL Ratio (\>4.0)0%3%2%15%7%21%Triglycerides
(\>200 mg/dL)13%13%12%10%5%9%\
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Page 16\
LUPRON DEPOT 3.75 mg Package InsertPage 16 of 18in hematocrit, platelet
count, and LDH. In the hormonal add-back studies LUPRON DEPOT
incombination with norethindrone acetate was associated with elevations
of GGT and SGPT.Uterine Leiomyomata (Fibroids):Hematology: (See CLINICAL
STUDIES section.) In LUPRON DEPOT 3.75 mg treated patients,
althoughthere were statistically significant mean decreases in platelet
counts from baseline to final visit, the lastmean platelet counts were
within the normal range. Decreases in total WBC count and neutrophils
wereobserved, but were not clinically significant.Chemistry: Slight to
moderate mean increases were noted for glucose, uric acid, BUN,
creatinine, totalprotein, albumin, bilirubin, alkaline phosphatase, LDH,
calcium, and phosphorus. None of these increaseswere clinically
significant.PostmarketingDuring postmarketing surveillance, the
following adverse events were reported. Likeother drugs in this class,
mood swings, including depression, have been reported. Therehave been
rare reports of suicidal ideation and attempt. Many, but not all, of
thesepatients had a history of depression or other psychiatric illness.
Patients should becounseled on the possibility of development or
worsening of depression duringtreatment with LUPRON.Symptoms consistent
with an anaphylactoid or asthmatic process have been rarelyreported.
Rash, urticaria, and photosensitivity reactions have also been
reported.Localized reactions including induration and abscess have been
reported at the siteof injection. Symptoms consistent with fibromyalgia
(eg: joint and muscle pain,headaches, sleep disorder, gastrointestinal
distress, and shortness of breath) havebeen reported individually and
collectively. Other events reported are:Cardiovascular System --
Hypotension, Pulmonary embolism; Hemic and LymphaticSystem - Decreased
WBC; Central/Peripheral Nervous System - Peripheral neuropathy,Spinal
fracture/paralysis; Musculoskeletal System - Tenosynovitis-like
symptoms;Urogenital System - Prostate pain.See other LUPRON DEPOT and
LUPRON Injection package inserts for otherevents reported in different
patient populations.OVERDOSAGEIn rats subcutaneous administration of 250
to 500 times the recommended human dose,expressed on a per body weight
basis, resulted in dyspnea, decreased activity, andlocal irritation at
the injection site. There is no evidence that there is a
clinicalcounterpart of this phenomenon. In early clinical trials using
daily subcutaneousleuprolide acetate in patients with prostate cancer,
doses as high as 20 mg/day for up totwo years caused no adverse effects
differing from those observed with the 1 mg/daydose.\
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Page 17\
LUPRON DEPOT 3.75 mg Package InsertPage 17 of 18DOSAGE AND
ADMINISTRATIONLUPRON DEPOT Must Be Administered Under The Supervision Of
A Physician.Endometriosis: The recommended duration of treatment with
LUPRON DEPOT 3.75 mg aloneor in combination with norethindrone acetate
is six months. The choice of LUPRON DEPOTalone or LUPRON DEPOT plus
norethindrone acetate therapy for initial management of thesymptoms and
signs of endometriosis should be made by the health care professional
inconsultation with the patient and should take into consideration the
risks and benefits of theaddition of norethindrone to LUPRON DEPOT
alone.If the symptoms of endometriosis recur after a course of therapy,
retreatment with a six-month course of LUPRON DEPOT monthly and
norethindrone acetate 5 mg daily may beconsidered. Retreatment beyond
this one six-month course cannot be recommended. It isrecommended that
bone density be assessed before retreatment begins to ensure that values
arewithin normal limits. LUPRON DEPOT alone is not recommended for
retreatment. Ifnorethindrone acetate is contraindicated for the
individual patient, then retreatment is notrecommended.An assessment of
cardiovascular risk and management of risk factors such as
cigarettesmoking is recommended before beginning treatment with LUPRON
DEPOT and norethindroneacetate.Uterine Leiomyomata (Fibroids):
Recommended duration of therapy with LUPRON DEPOT 3.75 mg isup to 3
months. The symptoms associated with uterine leiomyomata will recur
following discontinuation oftherapy. If additional treatment with LUPRON
DEPOT 3.75 mg is contemplated, bone density should beassessed prior to
initiation of therapy to ensure that values are within normal limits.The
recommended dose of LUPRON DEPOT is 3.75 mg, incorporated in a
depotformulation. The lyophilized microspheres are to be reconstituted
and administeredmonthly as a single intramuscular injection. For optimal
performance of the prefilleddual chamber syringe (PDS), read and follow
the following instructions:1. To prepare for injection, screw the white
plunger into the end stopper until thestopper begins to turn.2. Hold the
syringe UPRIGHT. Release the diluent by SLOWLY PUSHING (6 to 8seconds)
the plunger until the first stopper is at the blue line in the middle of
thebarrel.3. Keep the syringe UPRIGHT. Gently mix the microspheres
(particles) thoroughly toform a uniform suspension. The suspension will
appear milky.4. Hold the syringe UPRIGHT. With the opposite hand pull
the needle cap upwardwithout twisting.5. Keep the syringe UPRIGHT.
Advance the plunger to expel the air from the syringe.6. Inject the
entire contents of the syringe intramuscularly at the time of
reconstitution.The suspension settles very quickly following
reconstitution; therefore, LUPRONDEPOT should be mixed and used
immediately.NOTE: Aspirated blood would be visible just below the luer
lock connection if a bloodvessel is accidentally penetrated. If present,
blood can be seen through the transparentLuproLoc™ safety device.\
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Page 18\
LUPRON DEPOT 3.75 mg Package InsertPage 18 of 18AFTER INJECTION7.
Withdraw the needle. Immediately activate the LuproLoc™ safety device by
pushingthe arrow forward with the thumb or finger until the device is
fully extended and aCLICK is heard or felt.Since the product does not
contain a preservative, the suspension should be discardedif not used
immediately.As with other drugs administered by injection, the injection
site should be variedperiodically.HOW SUPPLIEDLUPRON DEPOT 3.75 mg is
packaged as follows:Kit with prefilled dual-chamber syringeNDC
0300-3641-01Each syringe contains sterile lyophilized microspheres,
which is leuprolide incorporatedin a biodegradable copolymer of lactic
and glycolic acids. When mixed with diluent,LUPRON DEPOT 3.75 mg is
administered as a single monthly IM injection.Store at 25°C (77°F);
excursions permitted to 15-30°C (59-86°F) \[See USP ControlledRoom
Temperature\]Rx onlyU.S. Patent Nos. 4,652,441; 4,677,191; 4,728,721;
4,849,228; 4,917,893; 5,330,767;5,476,663; 5,575,987; 5,631,020;
5,631,021; 5,716,640; 5,823,997; 5,980,488; and6,036,976.Other patents
pending.Manufactured forTAP Pharmaceuticals Inc.Lake Forest, IL 60045,
U.S.A.by Takeda Pharmaceutical Company LimitedOsaka, JAPAN 541TM-
Trademark® - Registered Trademark(No. 3641)03-5372-R18; Revised: August,
2004©1990-2004, TAP Pharmaceutical Products Inc.\</html\