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Group leader's mema to the !'IDA file for Lupron Depot
NDA: 20-263

Date:

3/26/93

We have a minimally adequate data base to warrant approval of
this depot form of a previously approved product. Neither of the
two pivotal studies could be controlled because the disorder can
not go untreated, and no alternative treatment outside this drug
class exists. We can be confjdent that hormonal and short term
clinical responses will reasonably predict long term clinical
benefits, but in the absence of any better approach we must be
willing to approve this therapy before those outcomes are
established.
It is regrettable that all we have is a post hoc analysis of a
multi-center "free for all" study on one hand, anr! a 22 child
prospective study with interim data available only from the six
month time point, on the other. The very limited pharmacokinetic
data come from this second study. This did not consist of a
systematic dose ranging ~esign, but was, in effect, an
examination of a pre-selected dosing nomogram. Three strata of
body weights were chosen and a single total dose was selected for
each stratum. The basis for each stratum's dosage was previous
experience with Lupron in~ection and depot, particularly the
published report of Kappy and Parker "suggesting that the monthly
depot dose should be in the 300 mcgjkg range". Notably, it was
found that trough plasma levels were fairly consistent at 4, 12,
and 24 weeks within each stratum. However, the group average
trough levels varied substantially (.77+.033, 1.25+1.06, 1.59+.65
for, respectively, the three groups in order of increasing
weight). The impression developed that once hormonal downregulation has been achieved that the dose could be maintained
indefinitely despite the child's increasir.g body weight. There
must be concern that this may not be true part..icularl:y for
children starting treatment at the lowest recommended dose. The
revised labeling adequately addresses this point, and if
monitoring of hormonal responses is performed as recommended,
escape from control should be detected.
There is really no doubt about efficac\. Hormonal downregulation was consistently achieved and growth rates were
significantly reduced compared to baseline. What we do not have
are data to allow more dosage precision. Practically speaking,
it would appear that the recommended dosages provide a margin of
bio~hemical efficacy which should down-regulate gonadotropin
secretion of virtually all children with central precocious
puberty. continued monitoring is an additional safeguard. There
is concern that this margin is thin for the children in the
lowest weight stratum and will tend to get thinner as they grow.
I believe that these defects are adequately addressed in the
labeling and the phase IV studies which are conditions for
•

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approval. Presently, there are no significant safety concerns
about the active agent although the theoretical problems with
reprodnctive function must await resolution with long-term
follow-up of the cohort. Ther·e does appear to be a higher than
expected frequency of local rElactions that is likely due to the
vehil.:le. This fs not a trivial problem since several abscesses
resulted. The labeling adequately warns of this problem, but the
Agency should continue to monitor this adverse reaction
carefully.

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Recommendation:
NDA approval with the conditions described in the currently
c;rculating approval letter.

•

Alexander Fleming, M.D.

-_,,- · _1.

HFD-510
JiFD-510

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JAN

6 1993

MEDICAL OFFICER'S REVIEW OF
A NEW DRUG APPLICATION

NDA #20-263
Lupron Injectable Dosage Forms
for Precocious Puberty
TAP Pharmaceuticals
I'

~

TABLE OF CONTENTS
Section - Title - page
1 Title and General Information - page 1
3
4
5
6

Material Reviewed- page 4
Chemistry/Manufacturing Controls -page 5
Animal Pharmacology/Toxicology- page 5
Clinical Background - page 5
6.1 Relevant human experience- page 6
6.2 Important information from related INDs and NDAs page 6
6.3 Foreign experience - page 10
6.4 Human Pharmacology, Pharmacokinetics,
Pharmacodynamics- page 10
7 Description of Clinical Data Sources - page 10
7.1 Study Type and Design/Patient Enumeration,
demographics, exposure - page 10
7.2 Post-Marketing Experience -page .11
8 Clinical Studies - page 11
8.1 Trials - page 11
8.1.1 Objectives and Ration,ale- page 15
8.1.2 Design page 15
8.1.3.1 Population- page 16
8.1.3.2 Endpoints -page 19
8.1.3.3 Statistical considerations- page 20
8.1.4 Result:s- page 20
8.1.4.2 Efficacy endpoint outcomes -page 20
8.1.4.3 Safety comparisons - page 27
8.1.5 Rev~ewer's Comments/Concluskms -page 27
9 Overview of Efficacy - Comparative results between studies
page 28
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10 Overview of Safety - page 
10.1 Significant/ Potentially Significant Events - page 29
10.1.1 Deaths - page 29
10.2 Other Safety Findings. - page 29
10.2.1 ADR Incidence Tables - page 29

11 Labeling Review - page 31
11.1 Description: page 31
1 1.2 Clinical Pharmacology:page 3 1
1 1.3 Indications and Usage: page 31
1 1.4 Contraindication - page 32
11.5 Warnings - page 32
11.6 Precautions - page 32
11.7 Adverse Reactions - page 32
11.8 Drug Abuse and Dependence - page 32
1 1.9 Overdosage is not a problem. - page 32
1 1.10 Dosage and Administration: - page 33
1 1.1 1 How Supplied - page 33
12 Conclusions page 33
13 Recommendations page 34

Fur--

 

 

 

NDA #20-263
Applicant: TAP Pharmaceuticals, Inc
Date Completed :January 5, 1993

1 Title and General Information
1.1 Leuprolide Acetate (LURPON) for Central Precocious
Puberty Medical Officer?s Review
1.1.1 20,263
1.1.2 M.O. Review 1
1.1.3 Submission May 29, 1992
1.1.4 Review completed: January 5, 1993
1.2 Drug name
1.2.1 Generic name leuprolide acetate
1.2.2 Proposed trade name 
LUPRON DEPOT-FED

Leuprolide acetate is a nonapeptide analog of
naturally occurring gondatropin releasing hormone or
LH-RH). The analog possesses greater potency than the natural

hormone.

1.2.3

The chemical name is 

prolinamide acetate (salt) with the following 'structural formula:

1.3 Takeda Abbott
1.4 Pharmacologic Categoryzconadotrophin analogue - 
analogue (LHRH or 

1.5 Proposed Indication:
CENTP PUBERTY 1



 

3"
4.6" . .

 

1.6 Dosage form(s) and route(s) of administration:

In the original approval of leuprolide for the palliative treatment of
prostate cancer a dose of 1 mg daily subcutaneous was used (1985);
the depot was 7.5 mg (28 days). The original doses used in
children were based on the doses used to suppress the male and they
were very inadequate. The depot doses are to be given under the
supervision of a physician; the daily injections can be given by a
parent or a health professional

Lupron Depot is supplied as a two-part package and is supplied in
two The vials contain sterile lyophilized microspheres
which when mixed with diluent becomes a suspension for 
intramuscular injection. The package includes: a single-dose vial of
sterile lyOphilized microspheres of leuprolide acetate either 3.75 mg
or 7.5 mg) incorporated into a biodegradable copolymer of polylactic
and acids and one ampule of diluent (1.5 ml.) for
reconstitution was included with each vial of drug. The diluent
includes 75 mg D-mannitol, 1.5 mg polysorbate 80 and water for
injection.

The total volume of injections never are more than 2 ml. and in most
cases the depot in the studies was reconstituted with 0.5 mL of
diluent per vial if two vials were mixed together and 1 mL of diluent
if only one vial of drug was administered. (amendment
OO4/November 23, 1992)

Lupron for injection is supplied as a sterile,?aqueous solutiion
intended for daily subcutaneous injection. It includes a 2.8 mL
multiple dose vial containing leuprolide acetate 5 mg/mL plus
preservative and water for injection,?

Recommended doses for both the depot and injection will be listed on
the labeling. 

1.7 DA Drug Classi?cation - standard

This submission is a new indication for an approved drug.
Leuprolide was approved for the palliative treatment of prostate
cancer in 1985 with daily 1 mg subcutaneous dosing, and in 1989

with the 7.5 mg depot. 2

 



E. 

 

1.8 Important Related Drugs;
a. NDA #19-836 - Applicant: Robert Wood Johnson
Pharmaceutical Company (Ortho) - Drug: Histrelin

Dose - 8 to 10 mcg/ kg/ day to be given subcutaneously.

b. NDA 20-109 - Applicant: Syntex - Drug Nafarelin
acetate/Synerel -
Dose - an intranasal delivery system



There are over 1000 analogues of the gonadotropins 
Two analogues were ?rst approved for the palliative
treatment of prostate cancer and include leuprolide (TAP) and
goserelin (ICI). buserelin, (Hoechst-Roussel), nafarelin, D-TRP6
(Roberts) are all ongoing studies in children with precociouus

puberty.

1.9 Related Reviews
see reviews related to CPP - NDA 19-836 and 20?109.
Prostate - NDA 19-752 (1 mg leuprolide) and 19836) 7.5 mg

depot.
Table of Contents
Section - Title - page
1 Title and General Information - page 1

3 Material Reviewed - page 4
4 ChemistJy/Manufacturing Controls - page 5
5 Animal Pharmacology/Toxicology - page 
6 Clinical Background - page 5
6.1 Relevant human experience - page 6
6.2 Important information from related INDs and NDAs - page 6
6.3 Foreign experience page 10-
6.4 Human Pharmacology, Pharmacokinetics,
Pharmacodynamics - page 10
7 Description of Clinical Data Sources - page 10



 

 

7.1 Study Type and Design/ Patient Enumeration, demographics,
exposure - page 10
7.2 Post-Marketing Experience - page 1 1
8 Clinical Studies - page 11
8.1 Trials - page 11
8.1.1 Objectives and Rationale - page 15
8.1.2 Design page 15
8.1.3.1 Population - page 16
8.1.3.2 Endpoints - page 19
8.1.3.3 Statistical considerations - page 20
8.1.4 Results - page 20
8.1.4.2 Ef?cacy endpoint outcomes - page 20
8.1.4.3 Safety comparisons - page 27 .
8.1.5 Reviewer's Comments/Conclusions - page 27
9 Overview of Ef?cacy - Comparative results between studies page 28
10 Overview of Safety - page 28
10.1 Signi?cant/ Potentially Signi?cant Events - page 29
10.1.1 Deaths - page 29
110.2 Other Safety Findings. - page 29
10.2.1 ADR Incidence Tables - page 29

1 labeling Review - page 31
11.1 Description: page 3 1
1.2 Clinical Phannacology:page 31
1 1.3 Indications and Usage: page 3 1
1 1.4 Contraindication - page 32
11.5 Warnings - page 32
1 1.6 Precautions - page 32
11.7 Adverse Reactions - page 32
1 1.8 Drug Abuse and Dependence - page 32
1 1.9 Overdosage is not a problem. - page 32
1 1.10 Dosage and Administration: page 33
1 1.1 1 How Supplied - page 33 3,
12 Conclusions page 33
13 Recommendations page 34

3 Material Reviewed: Volume 1.1 (1 of 15 volumes, Amendment 002,
July 28, 1992), Annual report (IND 12,835 September 29, 1992). Part of
data was also supplied on disk. Additional amendments included 004,
November 23, 1992; 005, November 24, 1992; Desk copy of study 90-053
provided on December 2, 1992. Volume 2.2 of 5 volumes. Information
Amendment of December 7, 1992 - 006. Amended chart December 23,
1992. 

 
i



1.

 

SITES PTS EFFICACY SAFETY
M90616 9 32 22 32

M90-05 3 3 8

365 226 365

Chemistry/ Manufacturing Controls

see Chemistry review

Animal Pharmacology/Toxicology

see Pharmac010gy review.

Clinical Background

Central Precocious Puberty (CPP) of either idiopathic or neurogenic
origin is de?ned as the appearance of any signs of secondary sexual
maturatiion before the age of eight years in females and nine years in
1males. It is seen more frequently in females. Males with CPP are
more likely secondary to neurogenic lesions. Sexual maturity is
considered precocious if secondary sex characteristics appear before
eight years of age in girls and nine years in boys. CPP has been
designated as an Orphan Disease with a frequency of approximately
one in 5000 to 10,000 children in the United States or 2000 new cases
per year. Isosexual precocity is much more common in girls and
idiopathic precocious puberty remains the most common ?nal
diagnosis in these girls. This submission is concerned only with the
treatment of central precocious puberty. Medical suppression of FSH
and LH and gonadal steroid secretion until the appropriate
chronological age is important in allowing continued skeletal
maturation prior to epiphyseal closure and thereby hopefuuy
improving the final adult height. There are currently two

gonadotr0pin analogs approved for

?le treatment of central precocious

puberty - nafarelin - Syntex, and. histrelin - RWJ Research Center.
The latter is now marketed by Roberts Pharm. The aim of treatment
is to adequately desensitize the gonadotroph cells to LHRH stimulation
so that gonadotr0pin secretion and gonadal stimulation are
suppressed. In addition to normalizing physical development,
effective treatment of CPP is also important because of the
problems associated with precocious physical
maturation prior to mental maturation.

Relevant human experience







n1: 

 

The analogs ?rst approved were for the palliative treatment
of prostate cancer and included Leuprolide (TAP) in 1985 (daily 1
mg sc). The depOt form was approved in 1989. Other analogs
include: goserelin/Zoladex (ICI) - approved for prostate cancer
treatment. nafarelin/Synerel (Syntex) - approved for CPP in 1991,
and histrelin/Supprelin - RWJ Pharm approved in 1990.? Ongoing

Histrelin is thought to be 210 times more potent than the natural

analog,

Leuprolide 18 only 20 times as potent a the natural This lower
potency is an important consideration in reviewing the ojcomes of
children with central precocious puberty.

 

The sponsor ?rst submitted a NDA for the treatment of CPP on
September 21, 1988 and was withdrawn in April 17, 1990. At the
time the sponsor had just begun using the depot formulation and it
was agreed to look at a small study of CPP children monitored
carefully using the depot formulation. This is the third new 
indication for Leuprolide.

6.2 Important information from related INDs and NDAs .

Over 1000 analogues of the gonadotrophins have been
following the initial isolation and structural elucidation of
the decapeptide by Schally and co?workers in 197 1. These
superactive stimulatory analogues were ?rst designed to
improve therapy with gonadotrophins but proved to paradoxically
desensitize the pituitary and suppress secretion of gonadotrophins
and a secondary reversible inhibitiop of gonadal function.

The ?rst strurtural elucidation was the LHRH decapeptide was done
by Schally and co?workers in 1971 at the Salk Institute (Shally. Am
J. Ob More than 1000 analogs have been
following this isolation Superactive stimulatory analogs
were ?rst desig 1ed to improve gonadotrophin therapy but proved to
paradoxically desensitize the pituitary by suppressing gonadotropin
secretion and depleting reserves. This results in loss of gonadal
stimulation and consequent reversible attentuation of gonadal
function. -

Central Precocious Puberty (CPP)

12$

 

CPP is caused by the premature activation of the hypothalamic?
gonadal axis. 98.8% of normal American girls start puberty between 
the ages of 8 and 13 (average age of 11) with black American girls 
advancing earlier during the ?rst 3 stages of puberty. The 
initial changes of puberty are usually seen in breast development,
which may not be completely reversible. American males are
approximately 6 months behind the females with 98.8% of boys 
entering puberty between the ages average 
age of 1 1.6 years. The ?rst indication of puberty in boys is usually
growth of the testis. Females usually gain 25 cm and males 28 cm
between t' onset of puberty and cessation of growth. Major
conuibutions to the understanding of growth have been made by
Tanner and his associates. (see Ann Human Biol 3: 109, 1976; a
growth chart is attached). Utilization of the Tanner Classi?cation of
developmental stages has simpli?ed and quanti?ed the evaluation
of puberty. Tanner's Stages in the girls consider breast and pubic
hair development and in the boys includes testicular, penile and
pubic hair development. An example of Tanner staging is included in
appendix.

Historical Treatment of CPP

It is important to differentiate premature activation of the
gonadotropin pulse generator from independent types
of isosexual precocity. True central precocious puberty occurs when
there is premature, sustained activation of the hypothalamic pulse
generator. Luteinzing hormone releasing hormone analogs or
Gonadotmphin releasing Hormone represent a
signi?cant advance in the therapy of CPP by suppressing premature
secretion of gonadotropins and gonadal steroids.

A variety of hormonal interventions has previously been used for
the treatment of CPP and none has been entirely satisfactory or
effective in improving final height as well as down regulating the
hypothalamic-gonadal axis. Previous clinical approaches have 1-
included no treatment, or treatment with either cyproterone acetate, 
medroxyprogesterone (MPA) or danazol. None of these therapies is
thought to improve the final height of these children. Both of these
clinical interventions have bad side effects. Suppression of gonadal
steroid secretion or action until the appropriate chronological age is
essential for continued skeletal maturation prior to epiphyseal
closure so that normal adult height may be achieved. Effective
treatment of CPP is also important because of the important

 problems associated with precocious physical
maturation prior to emotional maturation. The use of computerized
tomography of the head has revealed a much higher incidence of
hypothalamic hamartomas as a cause of CPP than was previously
suspected.

- Premature sex steroid secretion significantly compromises expected
final height. Data from two observational series is included in the
appendix of the sponsor. The series by Dr. Jolly of 69 children prior to
the age of ten years with 43 CPP (36 girls) in which the final heights
were available in only 8 of the girls and averaged 58.8 inches or 149.4
cm. The genetic height potentials of these children mid-parental
height) were not included. The second series by Thamdrup and
Danish included a mixture of children but probably 56 of these
children had CPP and were not treated. The individual and mean
?nal height of the children fell well below the sex adjusted mid-
parental height .

The following markers commonly used in studying ef?cacy in
children with CPP:

Growth Markers:

1. Growth velocity is measured in cm/yr. and determined over at
least 6 month intervals. Responses measured over longer periods of
time are more reliable. A growth spurt in females is noted at the
time period consistent with Tanner Stage 2 of breast development -
the earliest marker of development in the female. The accelerated
range puberty should slow to the prepubertal
growth velocity of less than 7 cm per year. By slowing the annual
rate of growth, epiphyseal fusion is delayed and ?nal height is
presumably improved. 5
2. Another criterion of effectiveness and growth a8sessment is:

BA (Bone Age determined from hand x?rays. The normal bone age
divided to the chronological age ratio should be appro?mately one.
The ratio of BA change to CA change over a set period of time is
used to assess the rate of premature development.

3. Calculation for predicted height is irnprecise in children who
already do not ?t the normal development tables and cannot be
calculated easily on data accumulated over a period of time less than
1 year. The final assessment of predicted improvement in height
requires observation of these children as they reach adulthood and 8

?1

. .. it. 

are compared to their mid-parental heights. The final predicted.
heights depend on many factors including the bone age of the child at
the initiation of therapy, accuracy of bone age reading, and accuracy
of modifications of methods USGU. to determine these numbers. All
CPP studies have attempted to demonstrate an improvement in the
predicted height measurements with treatment. None of the studies
has yet demonstrated the ?nal heights in these children.

In all of these parameters if there is no change it suggests that the
treatment is partially effective and the growth has at least been
stopped.

BIOCHEMICAL ENDPOINTS

1. Pituitary hormones One of the primary endocrine parameters
used to assess biochemical responses to therapy are plasma levels of
gonadotropins: Luteinizing Hormone (LH) and Follicle Stimulating
Hormone (FSH).

2. A LHRH (LH releasing hormone) or stimulation test (also
called a FACTREL test) utilizes the native peptide to assess adequacy
of down-regulation of LH and FSH secretion. This test is also a
standard measurement of maximum responsiveness as well as a
measurement of the reserve of the pituitary. Injection of 100 to 140
ug doses in adults and normal adolescents results in a 3 to 10 fold rise
of plasma LH over basal levels by 30 minutes. There is a similar rise
in FSH at 45 minutes. Most investigators measured the peak or
maxitnum level attained in the LHRH test i.e. the delta or the peak
level from the basal level. It has been suggested that overnight

monitoring is a more sensitive measurement of gonadotropin reserves.

Dr. Crowley used a stimulated peak of 8 (both LH and FSH) as

. demonstrative of adequate suppression. Many pediatric

endocrinologists do not routinely include this test because of its
expense. In study 90-5 16 the children were tested 'at one month for
adequate suppression; previous studies have used 3 months initially.

3. Estradiol levels should be less than 20 pg/ml to re?ect an
adequate therapeutic effectiveness. The levels of estradiol are
dependent on the maturation of follicles which can be very variable in
these children. This level was within the lower limits of detection in
these studies. Levels of estradiol in Tanner stage 1 is <9 - 20 pg/mL.
Not all girls have elevated estrogen levels despite the presence of
other signs of precocious puberty.

 

L.

 

4. The Testosterone level is a very sensitive marker in boys and
with adequate treatment it should be in the prepubertal range.

Appropriate levels of testosterone in Stage 1 Tanner are between ..
<10 - 22 

6.3 Foreign experience

None of the present data was submitted from foreign studies.
Leuprolide is marketed in many foreign countries including Canada,
France, Germany, and the United Kingdom.

6.4 Human Pharmacology, Pharmacokinetics, Pharmacodynamics
leuprolide acetate is not active when given orally. The 
bioavailability of leuprolide by subcutaneous administration is
comparable to the intravenous administration. It has a plasma half-
life of approximately 3 hours. see earlier reviews of leuprolide and
pharmac010gy review.

It is unique to rats that the gonadotropin analogs appear to cause
adenomas of the pituitary, adrenal and pancreas. There does not
appear to be a similar problem in humans.

7 Description of Clinical Data Sources

7.1 Study Type and Design/ Patient Enumeration, Demographics,
Extent of Exposure

This submission provides material from 2 multicenter open,
individual-controlled studies - 906 16 and 90-053.

The core of this NDA submission represents the interim analysis of 32
children in study 90-5 16 treated for at least six months with
leuprolide acetate Depot but also includes the data compiled for NDA
19-010 and withdrawn in April 17, 1990. This study which is
ongoing contains data from both subcutaneous and depot
Leuprolide acetate use.

SITES PTS EFFICACY SAFETY
M90-S 1.6 9 32 22 32
M90-053 38 365 226 365

10

TOTAL NUMBER OF PATIENTS IN SUBMISSION

(INCLUDING BOTH STUDIES) 1
LENGTH OF EXPOSURE 171?s EVALUATED 
MONTHS SAFETY EFFICACY 
>60 4 4 
>48-60 22 13
>36-48 32 23 I
>24-36 so 54 
>18-24 48 35
>12-18 63 37
>6-12 79 49
>3-6 30 17
6 26 16
TOT 384 248

(for 13 the duration of exposure is unknown)

The ratio of females to males in 90?5 16 was 10:1; the ratio in 90-
053 was 2:1. The time interval between diagnosis of CPP and
initiation of treatment in these children was usually one to two years.
The depot formulation of leuprolide acetate became available in 1988
and at that time 67 children in the 90-053 study switched from the
daily formulation to this formulation. Both studies included children
of caucasian, black, Hispanic and Oriental racial origins. Among
patients for whom race was provided, 83% were Caucasian, 7% were
black, 8% were Hispanic, and 1% was Oriental.

.2 Pom-Marketing Experience:
Leuproh'de has been approved for treatments where the suppression
of gonadal steroids is important. It was ?rst approved for the
palliative treatment of prostate cancer. The second approval for
leuprolide was for the depot formulation as a medical castration for
the treatment of Stage prostate cancer. It has also been approved
for the treatment of endometriosis. 3

8 Clinical Studies

8.1 Trials
The data for this submission consist of two multicenter trials.
Study 90-5 16 includes data using only depot formulation while the
second study, 90-053, includes children treated with both depot and
subcutaneous formulation. Most of the children were changed to the
depot when it was available in 1991. The review will include the
core depot study (A) as 90?5 16 TAP sponsored and the individual
investigator sponsored studies (B) as 90-053. For this submission,
data from the first six months of therapy for the 22 patients from
90?5 16 were combined with up to 5.3 years of data from 90-0531.l

gun . .. .- .- .. .. .. . 

 

The sponsor has combined some of the material in tables. 92
children have now received only depot formulation of leuprolide.
Efficacy endpoints were the same for both studies.

(A). 16)
Study done under IND 
Ten physicians were recruited by TAP Pharmaceuticals Inc. for

participation in this study. Nine of the ten applied for and received

authorization from his/ her Internal Review Board (IRB) and have
tested and treated children under this program. Each of these nine
primary investigators listed one (Reiter) to eight (Conte) physicians as
subinvesu'gators for their site. 8 of the sites have partic1pated in both
studies. This study will eventually include 50 patients. These data
represent an interim analysis. 

Patients were assigned a 3-4 digit patient number. The ?rst one or
two numbers were determined by the site number and patient
numbers were assigned sequentially as a patient underwent
preliminary testing.

Investigator Site No.
Bercu
Bloch
Burstein
Chalew
Conte
Hintz
Kappy
Lee
Pescovitz
Reiter



 

16 3
Investigator Number Evaluated Patients Evaluated
Safety Efficacy for Safety Only 

Bercu 3
Bloch 2
Chalew
Come 4
Hintz 6
Kalimv
Lee 6
Pescovitz
Reiter

(1) 105

(1) 406
(4) 503, 506, 507, 508
(3) 612, 614, 615



(1) 912
12





1.15..

 

'1
,1
This study includes 22 children who have completed the first 1

6 months of therapy and another 10 who have (at this interim 
review) not yet completed six months of therapy. It is an open
study using the depot formulation under the sponsor's protocol
(TAP). These children were treated only on depot formulation.

This study is continuing and will eventually include 50 children. I
However, for this submission, an interim analysis was done. 
This was based on a total of 32 children; 22 who completed the

?rst six months of therapy were evaluated for ef?cacy and

safety and 10 who had not yet completed six months of therapy

were evaluated for safety only. Thirty-one of the children

continue with therapy. Drug was discontinued in one of these

children due to noncompliance to the visit schedule.

The dose of leuprolide acetate for depot suspension was started
at 300 mcg/kg (minimum 7.5 mg) intramuscularly 
with adjustments of 3.75 mg upward, if necessary, at
subsequent clinic visits based on physical and laboratory
parameters. The doses ranged from 3.75 to 17.20 mg or a
median of 15 mg once a month for males and 7.5 mg for
females.

Prior to acceptance in the study, children were tested for clinical
evidence of CPP and for pubertal response to a stimulation
test. If the stimulated lu teinizing hormone (LH) reached 10 
and the bone age was advanced one year beyond the
chronological age, the child quali?ed for study entry.

24 children three years of age or younger were treated with the
depot formulation for at least six months. The mean 
dose was 496 mcg/kg in this population. (see appendix)
Twenty-seven percent of children received a starting dose of 7.5
mg while 36% received 1 1.25 mg and the remaining 36%
received 15 mg. Twenty three of these children were in study
90-053. The original doses of 10 mcg/kg used in children in
Study 90-053 was based on leuprolide doses used in adult men
with prostate cancer - 7.5 mg every 28 days for the depot or 1
mg sc daily. These doses were clearly inadequate for most
children. When study 90-5 16 was initiated the dose of 300
mcg/kg or a minimum of 7.5 mg depot was chosen based on the
previous data from 90-053. -

13

7'

None of the gonadotropin analogs have had to be increased with
growth of the child; but continued evaluation of suppression
twice is a year is recommended to ensure continued appropriate
down-regulation of the gonadotrcpins. .

B. Trial 
(see appendix for list of investigators and IND 

There were 39 investigative sites included in this open. study
that utilized both the daily subcutaneous formulation and the
depot formulation under the guidance of the individual
investigator's IND and protocol. Enrollment in this study was
started in November 1985. The formulation, the dose and the
frequency of the injection were based on the individual
investigator protocols. These data were collected retrospectively
and the sites were not monitored by TAP Pharmaceuticals Inc.
Study differed in that each investigator conducted his
or her own study under his or her own IND and protocol. Each
protocol demonstrated varied requirements and the uniqueness
of the investigator's assessment of the individual patient became
evident as the study progressed. Patients who had been started
on daily subcutaneous doses of Ieuprolide acetate where
switched to depot. There was variability in objective and
subjective parameters. The need for therapeutic intervention
was often assessed based on clinical and secondary
sexual characteristics.

A total of 365 children were entered into this Study; 226
children evaluated for ef?cacy and 365 for safety. This included
286 females and 77 males and 2 with sex unknown. It was an
open study and the formulation, dose, and frequency of the
injections was based on the individual protocols. Initially in
these studies many of these children were not suppressed
rapidly because the doses originally used of leuproiide were too
low. and/ or the investigators did not appreciate or always agree
in the importance of rapid and consistent down-regulation.

Some of the data included in 90-053 were originally submitted
in 1990. The original submission at that time included 62
children - 48 girls and 14 boys. A total of 1 11 patients were
em'olled but only 62 were included in one or more efficacy
analyses in children treated between 107 and 747 days with
nine patients having ?nished treatment at the time of that
submission. These children were treated with a subcutaneous
dose of 4 to 50 ug/ kg and the defined dose recommended by4

 



the sponsor at the end of treatment was 30 ug/ kg/ day for girls
and 20 ug/kg/day for boys. The advisory committee at that
time did not believe that there were adequate data to blish I
the effectiveness of the drug for the treatment of chil with
CPP. One submission in 1992 was previously withdrawn. 
8.1.1 Objectives and Rationale
I


The speci?c objectives of these studies were to demonstrate that

this gonadotropin releasing factor analog, leuprolide, would

effectively suppress the prematurely activated gonadotropin

system in children with central precocious puberty. . .
Suppression of the gonadotropins would halt the signs and

results of precocious puberty.

8.1.2 Design
Design of Studies

The two studies (90-516) and (90?053) were both
multicenter studies assessing the safety and ef?cacy of
leuprolide acetate in the treatment of CPP. Study 90-5 16
includes data using only depot formulation while the second
studies includes children treated with both depot and
subcutaneous formulation. Most of the children were changed to
the depot when it was available in 1991. There was a total of
38 investigative sites and eight of the sites participated in both
studies 90-516 and 90-053. Altogether 248 children were
evaluated for ef?cacy and 397 for safety from this study.

This patient population in both studies generally consisted of

children with central precocious puberty. Due to the uniqueness

in the protocols, patients' ages varied. The children were to

have developed secondary sexual characteristics consistent with

puberty, an advanced bone age, and either pubertal basal or

stimulated gonadotropin measurements. Estradiol levels may

or may not have been elevated in females, but testosterone 
levels were generally elevated in males. Patients with CPP with
central nervous system (CNS) lesions who met the above criteria
were also eligible for therapy.

The studies consisted of an open treatment period during which
patients received either daily injections of Lupron Injection or
injections of Lupron Depot as determined by the
investigator's protocol. The initial injection was 



 

 

Day 0 or Week 0, following Pretreatment procedures and
eval?ation (Day 0 is listed as Rx Day 1 in the Appendices of the

sponsor).

Pretreatment procedures and evaluau' ons performed during the
studies were somewhat similar and included a medical and
disease history, a menstrual history, physical examination that
included Tanner staging of breast, genitalia and pubic hair,
radiographs of the left hand and wrist for bone age
determinations, clinical laboratory determinations (hematology
and chemistry), and determinations of basal and stimulated
gonadotIOpins and sex steroids.

8.1.3 Description of Procedures

Both of these Phase 111, open, multicenter studies utilized
biochemical and physical measurements to evaluate the
effectiveness of suppression of gonadotropins by this analog in
children with central precocious puberty (CPP). -

8.1.3.1 Population, procedures

CPP was de?ned, as noted above, as the appearance of any
signs of secondary sexual maturation to include breast
enlargement, vaginal maturation, testicular and phallic
enlargement in boys and the development of pubic hair before
the age of 8 years in females and 9 years in males.

6

More Specifically, these criteria include: Tanner stages II to
for breasts (B), pubic hair (P), or genitalia basal and/or
peak stimulated gonadotropin levels, luteinizing hormone and
follicle stimulating hormone in the pubertal range; a pubertal
response to stimulation in a child, earlier than normally
expected. Pubertal stimulation was defined as a baseline
stimulated luteinizing hormone (LH) response that equals or
exceeds the baseline value by 10 using the Del?a assay.

The following qualified to be included in ef?cacy evaluation:
oFemale patients were less than 9.0 years of age on 

the day of study drug initiation and males were less than 10.0
years of age. 16

 

OPatients had a diagnosis of CPP. No children were excluded
based on results of baseline laboratory tests.

OPatients did not have growth hormone de?ciency,
hypothyroidism, or a history of irradiation to the CNS.

OPatients had not previously been treated with a analog.
OPatients received study drug for a period of at least one month.
All patien ts were evaluated for safety.

In study 90-516 Stringent entry criteria were used including a
stimulated peak LP. above baseline of 10 (Del?a assay). As
of December 15, 1.991, 102 children had been screened as stated
in the protocol. Of these, 59 were excluded because the failed
to meet entry criteria. Fifty?four (54) children did not qualify
because the stimulated LH level did not reach 10 L. Such a
high percentage of failures due to this criterion was not
anticipated when the physical examination showed a pubertal
state. However, many had peak LH values of 4?10 and the
investigators felt that these children did indeed have a form of
CPP. In several instances, the samples were split and sent to the
site's local laboratory for veri?cation of response. In all cases,
the local laboratory results re?ected the same conclusions noted
at the endocrine laboratory in Pittsburgh. One child (Lee 802)
was retested and quali?ed at a later time.

Also, if the bone age was not advanced one year beyond the
chronological age, the child did not qualify for the study. Two
children did not have advanced bone ages, and one child failed
both laboratory and bone age "riteria. Two children did not
qualify due to other reasons. An additional 1 1 children who
have been tested are either still in screening?or the parents have
not made the decision to enter the child into the clinical
program.

If any underlying disorder existed, primary therapy had
been undertaken and the patient had been stabilized for at least
one year prior to participation in this protocol. Ages were
restricted to males under 10.0 years and females under 9.0
years of age at the time of initial dosing. However, signs of
central precocity must have been documented before the age of
9.0 and 8.0 years males and females respectively. These 17

 

 

children demonstrated a bone age advanced at least one year
beyond the chronological age. The children each served as their
own controls similar to two previous studies of children. with
CPP e.g. histrelin and nafarelin.

Pretreatment procedures and evaluations performed during
the studies were similar. These included a medical and disease
history, a menstrual history, physical examination to include 
Tanner stages of breast, genitalia and pubic hair, radiographs of ..
the left hand and wrist for bone age determinations, clinical
laboratory determinations (hematology and chemistry), and
determinations of basal and stimulated gonadotropins and sex
steroids.

Patients were monitored according to the protocols. The
patients in 90-516 received a minirnurn of 7.5 mg of leuprolide
acetate for depot suspension once a month. To achieve the
higher doses for children who weighed over 25 kg, either the
3.75 mg or the 7.5 mg dosage forms were combined.

The dose of drug to be given was dictated by the child's weight.
For the initial dose, 300 mcg/ kg (minimum 7.5 mg) was
administered intramuscularly once a month. The original doses
used in children was 20 and 30 ug/kg which accounts for delay
in suppression in the early children in 90-053 study. It is
recommended that the initial doses be based on body weight as
follows37.5 kg 11.25 mg
37.5 kg 15 mg

After 8 weeks, if total down-regulation, as evidenced by a peak
LH not to exceed 1.75 at the Week 4 stimulation test,
is not achieved, the dose was to be increased by 3.75 mg. After
12 weeks of therapy, the dose was increased in the studies if
necessary particularly as monitored by the stimulation tests..

18

 n: .. - . - ..

STARTING DOSES M90-S 16
9?0 CHILDREN DOSE

27% 7.5 MG
36% 11.25 MG
36% 15 MG

Patients were followed for the first 12 weeks and then,
at least every three months for the ?rst year and every six
months thereafter until end of treatment. Drug will be

discontinued when an age appropriate for puberty is attained or

at the discretion of the investigator, patient or parent.

Study 90-053 was an open study that utilized both the daily
subcutaneous formulation and the depot formulation under the
guidance of the individual investigator's IND and protocol.

These data were collected retrOSpectively and the sites were not

monitored vigorously by TAP Pharmaceuticals Inc. The
formulation, dose, and frequency of the injections was based on

the individual protocc 

The initial depot dose for the patients in M-90-053 who
switched from the daily to the depot formulation was 1.22 to 15

mg. 92 children received only the depot formulation in P90-OS3

and the dose ranged from 3.75 to 17.2 mg.

226 patients, age ranged from 0.8 to 9.8 years. Of the 226
evaluable children, 29 were male, 195 were female,
and 2 were of unknown sex. Females were younger
than the males with respective mean ages of 6.1 years for
females and 6.3 years for males. The last 92 children who
entered into the study received only leuprolide acetate for depot
suspension.



8.1.3.2 Endpoints

Ef?cacy was assessed by suppression of gonadotropins and sex
steroids (where pubertal) to prepubertal levels, slowing of bone
age advancement, by a decrease in growth velocity and an
increase in predicted adult height, and by decreases or
stabilization in Tanner stages.

19

 

A,

 ..-- .. .

8.1.3.3 Statistical considerations

A statistical consultation was not requested. Each child served
as his or her own control. All p-values were based on two-
tailed tests. P90-053 with 38 investigators using both
subcutaneous and depot forms was a retrospective study with a
duration of treatment from 3 months to 5 years. M90-S 16
included 9 investigators and 32 patients on test drug using only
depot form. This was a prospective study on-going with a
duration of treatment of 6 months.

8.1.4 Results

The sponsor has submitted data from two studies, 90-5 16 -
depot formulation only and 90?053 with combined
subcutaneous and depOt formulation from individual
investigator initiated protocols.

8.1.4.2. Ef?cacy endpoint outcomes

A. In study 90616 ninety-?ve percent of the children (21 of
22) were suppressed by ?Week 4 - the time of ?rst evaluation.
Stimulated gonadotropins peaked at 1.75 or less and sex
steroids returned to the pre-pubertal range. For most patients,
Tanner staging remained unchanged or decreased during their
?rst 24 weeks receiving drug.

Bone age ratios remained during the
first 24 weeks of therapy. There was no increase in predicted

adult height. There was a decrease in the rate of growth.
a

Gonadotmpins

Twenty-two children had stimulation tests at baseline, and
at Week 4. wenty-one children also received the test at week
12. One child (Pescovitz 909) was also tested at Week 8 and
Week 20. The extra tests were necessitated by protocol which
required dosage changes.

Basal and stimulated results of LH and FSH are listed by

investigator in Appendix . Analyses of changes in
20



gonadotrOpin levels from baseline to each determination are
summarized in Table 5. Statistically significant decreases from
baseline for both basal and peak gonadotropins were noted.
Downregulation as evidenced by suppression of stimulated
gonadotropins, with the LH to not more than 1.75 was 
apparent by Week 4 in all but-one of the 22 children 

One child (Pescovitz 909) had the highest baseline levels. From 
Week 0 to Week 4, the baseline peak LH decreased from 81.7 to
2.1 At Week 8, although the basal level was in the same
range as at the Week 4 visit, the peak LH had increased (10.4
L) although her estrogen was suppressed. At Week- 24, the
peak LH was still above the suppression level (3.39 At
week 36 she was suppressed (15 mg dose) and at 20 months in
therapy is doing well. Amendment 005 - November 24, 1992
includes further information on this patient. She was 14 months
at baseline; her history is negative except for fall down a ?ight
of stairs with loss of consciousness 4 months prior to treatment.
Fhere is also a suggestion which has not been documented that
the regulation of younger or smaller children may be more
dif?cult.

Sex Steroids

At baseline, 15 of 20 females demonstrated pubertal estradiol
levels. Baseline estradiol levels ranged from <5 to 90 pg/mL
(mean 18.3 -S.E. 4.5). At Week 24, eaifzh patient's estradiol level
was <5 pg/mL which resulted in a statistically signi?cant change
from baseline. These changes are noted in Table 4 from the
submission.

Both of the males exhibited pubertal testosterone levels at
baseline. Baseline levels were 29-4 and 447 ng/dL which was
suppressed to 10 by week. 4. All of the children demonstrated
sex steroid levels in the prepubertal range. No female
demonstrated an estradiol level greater than 5 pg/mL and no
male exhibited a testosterone level greater than 10 ng/dL. Sex
steroids continued to be suppressed through Week 24 for all
patients. 21

. 11--

Growth Markers

At each study visit, assessments were made of height, weight,

Tanner staging, and menstrual history, if appropriate. ?1
Radiographs for bone ages were done at baseline and the Week ?1
24 visit. Radiographs of the left hand and wrist were provided

by the local site for bone age assessment at the Fels Institute,

Yellow Springs, Ohio utilizing the Fels methodology.

In study 90-5 16 the baseline bone ages for the 22 evaluable
patients in this submission ranged from 2.5 to 13.2 years (mean 
S.D.: 9.8 2.3). At Week 24, the 21 patients completing 24
weeks of therapy had bone ages ranging from 3.9 to 13.7 years
(mean S.D.: 10.8 2.2).

For 21 patients, no signi?cant mean change in this ratio of bone
age to chronological age and the ratio of change in bone age to
change in chronological age was noted from baseline through
Week 24. 

For the 19 childran with baseline and six month data, predicted
heights were calculated using the Bayley Pinneau method. Two
patients (Lee 8 12, Pescovitz 909) were not included in this
calculation because they had bone ages less than seven years, the
lower end of the Bayley Pinneau Tables. Predicted heights
decreased by 2.69 - 0.74 cm (mean 3.13.) from baseline to
Week 24. This was statistically significant, but may re?ect the
short time on the drug. The bone ages averaged 3.47 years
ahead of the chronological age in females and 4.94 years in males
at the end of treatment, as compared to 2.98 and 4.75 years,
respectively, at baseline. It is too soon in these studies to fully
determine the bone age changes in these children.

Tanner Stages

1



?1v?w-

v-

 

The staging was a subjective assessment based on guidelines. If
a range was given for the stage, the lower value was utilized for
analysis. No patient experienced an increase or decrease in
Tanner staging by more than one Tanner staging unit. Baseline
Tanner staging ranged from I to IV. Three patients (Bloch 203,
Kappy 701, 705) did not have Tanner staging done at Week 8,
due to misinterpretation of the protocol.

Success of therapy was de?ned as a decrease in Tanner staging
or maintenance of the baseline value.

Breast: The amount of ?brous tissue in the breast may be a
function of the amount of time that the tissue was present prior
to therapy, and may in?uence maintenance of breast size. Over a
24 week time interval, four or 21% of 19 females showed a
decrease in breast development. Thirteen or 65% of 20 remained
at the same Tanner stage and three or 15% of 20 showed an
increase in breast tissue. The sponsor rated the overall success

for this parameter as 85%,

Pubic Hair: Tanner staging of pubic hair was divided by sex for
analysis. Success was de?ned as for breast as noted above.

Genitalia: Tanner staging of genitalia was measured at each
study visit. Success was de?ned as for breast and pubic hair.
For the females the decreases in staging were observed in six or
35% of 17 patients over a 24 week interval. Thirteen or 65% of
20 remained at the same Tanner stage and one or 5% showed an
increase in Tanner staging. This represents a 95% success rate.

Baseline Tanner staging in males ranged from to (one at
each stage) with a 100% success rate in preventing advancement
to a higher stage.

Menses were de?ned as menstrual-like bleeding for three
consecutive days requiring prorection. six females were
postmenarchy at the time of starting treatment. Five reported
spotting or menses the first month of therapy. This could have
been estrogen withdrawal. No further menstrual bleeding was

23

 



 

 

noted. Four of the 14 females who were premenarchial prior to

therapy experienced a bleeding episode, either spotting or

menses during the ?rst month following the initiation of 1
therapy. This episode was thought to be related to the initial
stimulatory effect of the analog followed by estrogen
withdrawal.

At one site, two patients (Lee 802,812) were reported to have
spotting. This was described as a cyclic yellow vaginal discharge
with and without evidence of a bloody show. Although this was
recorded as spotting because of its cyclicity, the investigator did
not feel that this was menstrual spotting. 

Results from study 90-053:

Gonadotropins:
(See previous section for further explanation.)

Basal and stimulated results of LH and FSH

There were statistically signi?cant decrease noted from baseline
for both peak gonadotropins. The ?rst evaluation was done at 6
months and the assays were done at various sites.

Table 20 - 90-053 is attached. The peak FSH is 26.8
at: baseline and at 6 months is 6.3. 

The peak LH (ns84) at baseline is 42.9 and at 6 months is
1 1.4 M.

Sex Steroids: 

Estradiol 107) decreases from a baseline (at 22.9 pg/mL to
1 1.5 pg/mL at 6 month. The last value for 1 15 patients from a
baseline of 22.5 pg/mL is 9.5 pg/mL at 6 months.

Testosterone (n=16) decreases from a baseline of 360.5 ng/dL
and at 6 months is 52.1 ng/dL. The last value for 17 patients
from a baseline of 344.6 ng/dL to a treatment of 40.1 ng/dL at
6 months.

In evaluating the hormonal responses in these children it should
be remembered that the individual investigators used their 

 

?rv

 

L.

protocols and had assays performed in their own laboratories. In
addition the sensitivity of these assays has improved 0V er the

course of the study.



Growth Markers

During the ?rst six months of therapy, 82 children demonstrated
a signi?cant mean decrease of 1.86 cm/ yr. from baseline in their
growth rate. This continued with decreases in growth rate in
successive six month intervals thereafter.



The bone ages were read locally using radiographs of. the left
hand and utilizing the methodology of Greulich and Pyle. An
analysis of the delta delta CA demonstrated a decrease from
baseline in this ratio which became statistically signi?cant at 24
months in the combined data.

Tanner Stages

The success rate of each of the Tanner stages was similar to 90-
516 with success rates of 77% for the overall Tanner stages.

Return of Testicular Function

Two boys have discontinued therapy and were tested for
spermatogenesis 6 to 12 months after. Both demonstrated
active sperm, one with a sperm count within the normal range.

Additional information

For the depot formulation, one investigator (Garibaldi) did not
administer the drug on a basis consistently. Drug was
administered from 4 to 6 week intervals. This was done because
the physician wished to ensure that gonadal function was still
present following suppression. This physician was advised that
his dosing interval exceeded our recommended interval and he
would have to adhere to a dosing regimen. He
subsequently agreed to this restriction.

One investigator, (Homer) administered drug on a three week
interval to selected patients. 

25

 

 

 

 

.1 
In summary successful suppression was achieved in 95% of 
the children by Week 4 in 90-5 16. In addition in
studies, the majority of children demonstrated. decreases or 
stabilization in Tanner staging of breaSt, pubic hair, and i
genitalia compared with baseline. Menses ceased in all 

females by the end of the second therapeutic month. Growth

rates were slowed. However, six months of therapy was not

suf?cient to assess the impact of Leuprolide treatment on 
predicted adult height in 90-5 16. i

For the one child who did not fully suppress, it has been
hypothesized by the treating investigator and the pr?
investigator that the child's response was affecredby her
young age. This child, age 1.1 years at the time of initial
dosing, exhibited the highesr baseline values for Lil, FSH, and
estradiol of all the children. The immaturity of her pituitary
may have in?uenced her response to agoniSt therapy.

A premature termination was de?ned as a child discontinuing
therapy for any reason Other than age appropriate for puberty.
Ninety-one children are known to have terminated therapy.
Thirty-four children terminated from study participation
because they had reached an age appropriate for puberty as
determined by the parent or investigator. Fifty-seven (57)
children are known to have terminated prematurely.
Noncompliance was an issue, especially with the daily injection.
Seventeen patients discontinued therapy due to noncompliance.
This included those noncompliant with the visit schedule and
those for who?reasons for termination were listed as personal
or parental dE e. Eight children terminated therapy due to
adverse events. Two padentgdiscontinued therapy because of
what was described as ineffective therapy probably related to
the inadequate dosing early on. Thirty children discontinued for
other unspeci?ed or unknown reasons.

These studies demonstrated:

0 reduction of gonadotropins to prepubertal levels,

0 return of sex steroids when at pubertal levels to
prepubertal values, 

- slowing of linear grown velocity. 26

8.1 .43 Safety comparisons

In both studies all patients who were excluded for efficacy
were evaluated for safety analysis.

The safety comparisons of this injectable drug are comparable to
that seen with other analogs e.g. histrelin and nafarelin
with skin reactions, irritation and abscesses at injection site.
Additionally patients discontinued due to recurrent brain
tumor, headache and syncope, and erythema multiforme 
(considered possibly to be related to drug but rated niild).

8.1.5 Reviewer's Comments/ Conclusions of study Results 

The study 90-516 provides carefully monitored data on 22
evaluable children out of 32 demonstrating appropriate
suppression of gonadotropins and gonadal steroids with
leuprolide depot. Although slowing of growth velocity is
demonstrated in these children (see chart below) it is too soon to
assess the ?nal adult height in these children. The continuing
studies of 90-053 support the ef?cacy of the use of the injection
or depot formulation of leuprolide.

27

 

9 Overview of Efficacy - Comparative results between studies

 

 

 

 

 

 

 

 

 

 

 

 

 

 

SUMMARY 
STUDY - 90-5 16 90-05 3 DATA I
DEPOT AND INJECTION
PEAK 95% AVERAGE PEAK
1 MONTH 27.0 - BASELINE
>1.7s 6.3 6 MONTHS
SUPPRESSION
-
ESTROGEN 100% 22.9 - BASELINE
TANNER I mom 11.5 - 6 MONTHS
<9 - 20 03-3 
SUPPRESSION 

 

 

 

 
    
    

 

100% I 360.5 
40.1 - 6 MONTHS
1 month 

 

(370.15.40.01

85-10096


 

 

 

77%


 

 

 

 

 

 

 

Fa) (104) I
_b)10.64 ->4.33 (105)

 

decrease



 

11.53 6.50 I 1.86m?.

 

 

   
 

 

 

 

 

 

 

I1 INSUFFICIENT - LAST VALUE
TIME ro ASSESS - 1.5 decrease ->0.93
THIS 

 

 

Baeline estradiol levels ranged from <5 to 90 ngmL.
Prepubertal growth velocity 5 - 6 cm per year

5
There were a total of 22 (90-5 16) and 226 (90-053) children for a total of
248 evaluable for one or more clinical evaluable variables. 10 children in
5 16 were evaluable only for safety because their treatment was for 55
than 3 months. The predicted heights are not included since there has been
insuf?cient duration of treatment to determine this outcome.

10 Overview of Safety
All 32 children who had been enrolled in the treatment period
under this protocol as of December 15, 1991, were analyzed {gr

safety. Leuprolide acetate for depot suspension was found to be
safe in this pediatric population. None of the children
discontinued therapy due to an adverse event. Among events
considered to have a potential relationship to drug, vaginitis and
general pain were each experienced by two children. Other
potentially related events were limited. 

In study 90-5 16 adverse events were reported in 17 of the 22
patients Adverse events considered by the investigator
to have a potential relationship to study drug were reported in
three children. One was related to injection site

pain/ reaction and the others: were vaginal discharge and 
moodiness. A11 adverse .1 rated mild or moderate.

Concomitant Medications

All medications taken concomitantly with leuprolide acetate are
listed. Eleven children received other drugs. These drugs
included antibiotics, chemotherapeutic agents, antihistamines,
anticonvulsants, and many over?the?counter analgesics and cold
preparations. The multitude of drugs used is a 1 e?ection 0f the
concomitant problems of these children.

10.1 Signi?cant/ Potentially Signi?cant Events

10.1.1 Deaths There has been one recent death of child with
reSpiratory problems which appears to be unrelated to
leuprolide. Autopsy material is pending. Preliminarl?tlata
notes a normal pituitary on pathological evaluation.

10.2 Other Safety Findings. The most important problem is
inadequate dosing particularly in 90-053 by individual
investigators at the beginning of these studies. Inadequate
dosing can result in stimulation rather than suppression of the

gonadotroph.
10.2.1 ADR Incidence Tables

This table is taken from the submission: -
In two studies of children with central precocious puberty, in 2% or more of
the patients receiving the drug, the following adverse reactions were 29

 

 



reported to have a possible or probable relationship to drug as ascribed by
the treating physician. Reactions considered not drug related are excluded.

(Number of Patients)

(N: 398 Berger's:

Body as a Whole
General Pain 7 2
Integumentary SyStem
Acne/Seborrhea 7 2
Injection Site Reactions Including Abscess 20 5
Rash Including Erythema Multiforme 8 2
Urogenital System
Vaginitis/ Bleeding/ Discharge 7 2

In those same studies, the following adverse reactions were reported in less
than 2% of the patients.

Body as a Whole - Body Odor, Fever, Headache, Hypertrophy, Infection;
Cardiovascular System - SynCOpe, Vasodilation; Digestive System - 
Gingivitis, Nausea/ Vomiting; Endocrine System - Accelerated
Sexual Maturity; Metabolic and Nu tritionai Disorders - Peripheral Edema,
Weight Gain; Nervous System - Nervousness, Personality Disorder,
Somnolence, Emotional Lability; Respiratory System - Epistaxis;
Integumentary System - Alopecia, Skin Striae; Urogenitai System - Cervix
Disorder, Gynecomas tia/ Breast Disorders, Urinary Incontinence.

In summary:
Injection site reactions are the most common problem seen in all of

often have other problems secondary to central precocious puberty.
The vaginitis, vasodilation, emotional labih'ty, acne, and menstrual

in both girls and boys ichessary to assess the ultimate reproductive
function of these children. There appear to be no other drug
interactions.

30

11

Labeling Review

1 1.1 Description:

The description of the analog and the injection and depot forms in
which it is supplied are adequate. The doses are described in section
under Dosing. 

1 1.2 Clinical Pharmacology:

The Sponsor notes the physiologic effects with chronic administration
but some changes are needed in this section.

The section should include the time frame of suppression of the basal
gonadotIOpins e.g. 1 month. The reference to changes in skeletal
growth and organ growth refer to other studies and not this
submission.

1 1.3 Indications and Usage:

Indications for use are appropriate and include confirmation of
diagnosis of CPP, advancement of bone age beyond chronological age
by one year. The baseline evaluations should include height and
weight measurements, gonadal steroid levels, adrenal steroid level to
exclude congenital adrenal hyperplasia., beta human chorionic
gonadotrOphin level to rule out a chon'onic gonadotrOpin secreting
tumor, rule out other steroid secreting tumors, and a computerized
tomography of the head to rule out intracram?al tumors.

The recommended starting dose is 0.3 mg/ kg (with a minimum 7.5
mg) administered as a single intramuscular injection. The starting
dose will be dictated by the child's weight.

25 kg 7.5 mg
>25?37.5 kg 11.25 mg
37.5 kg 15 mg

If total down regulation is not achieved, the dose should be titrated
upward in increments of 3.75 mg per month to a maximum of 15 mg
per month. This dose will be considered the maintenance dose.

The label will read that ?the ?rst dose found to result in adequate
down regulation can probably be maintained for the duration of
therapy in most children. However, there are insuf?cient data to
guide dosage adjustment as patients move into higher weight 
categories particularly after beginning therapy at very young ages
and low dosages. It is recommended that adequate down regulatiqxi

 



be verified in such patients whose weight has increased significantly
while on of December 29, 1992)

The lyophilized microspheres are to be reconstituted and
administered as a single intramuscular injection, in accord
with the following directions: 

'1 1.4 Contraindications:

This drug is contraindicated in women who are or may become
pregnant. children who demonstrate hypersensitivity to agonist
analogs of any of the excipients of the products. The anaph 'lcctic
reaction to is not ad.

11.5 Warnings:

The importance of noncompliance with drug regimen is noted. This
perhaps should be strengthened since inadequate dosing could
actually worsen this disorder.

11.6 Precautions
11.6.1 General: patients with known allergies to ingredients
and erythema and induction at the injection. site. 
1 1.6.2 Clinical Pharmacology
11.6.3 laboratory tests
1 1.6.4 Drug interactions - None anticipated or known
1 1.6.5 Carcinogenesis, mutagenesis, impairment of fertility: A
two year carcinogenicity study in rats and mice. Notes the
lack of demonstrable pituitary abnormalities in Leuprolide
treated adult patients. Notes that clinical studies to date are
not completed to assess the full reversibility of fertility
suppression.
1 1.6.6 Pregnancy category is noted.
1 1.6.7 labor and delivery - should not be used
1 1.6.8 Nursing momers - should not be used.
1 1.6.9 Pediatric use - information for parents included.
related to irritation at injections site and the sudden down
regulation of gonadal steroids.

1 1.7 Adverse Reactions are reported in 398 children. As noted
above the most common reactions are injection site experiences (2 9/0?
and vaginal bleeding and/ or discharge 

1 1.8 Drug Abuse and Dependence is an unlikely problem.
1 1.9 Overdosage is not a problem. -

32

 




mm .. mm,? 
1 1.10 Dosage and Administration: The depot must be administered 
under the supervision of a physician and the injection form can be
administered by a patient/parent or health care professional. a

The label appropriately notes the importance of monitoring with a 
stimulation test until the down regulation achieved and the

monitoring of bone age every 6 to 12 months. If down regulation is 
not achieved the dose should be titrated upward in increments of 3 75 
mg per month to a maximum of 15 mg per month i

The recommended depot dosing schedule should continue to be 28
days rather than 1 month.

1.1.1 1 How Supplied: Leuprolide for children is provided in either
LUPRON Depot - 2 - for a intramuscular injection
or Lupron injection for a single subcutaneous injection.

12 Conclusions

Sponsor?s conclusions:

material from 39 investigators who varied their protocol and
conception of appropriate therapy. In general when the children
received the appropriate dose their gonadal steroids are
suppressed, grOWth velocity decreases; and pubertal
development for the most part IS arrested. With aggressive
treatment and appropriate monitoring these children were
suppressed as seen in Study A 90-5 16.

Medical Of?cer's conclusions:

 

 

had not been treated for 6 months but were included in the
safety data. In addition they have provided data from 39
individual protocols, Study 90-053, of over 5 years of treatment
of children with CPP.

The data 90-5 16 demonstrated that the depot forniulation when
used and dosed appropriately can effectively suppress the
gonadotropins and the gonadal steroids within 1 month.

Previous submissions have demonstrated suppression at 3
months.

LUPRON depot offers an acceptable alternative for children with
CPP. It is the only depOt formulation available for these
children. Although it is a less potent analog, the doses
used in the 90-5 16 study demonstrate that in each of the
children the gonadotropins and gonadal steroids were rapidly
suppressed, growth velocity slowed and a halt to the progression
of the secondary sex characteristics.

There appear to be few regulatory problems. The labeling
should clearly state the dosage for this analog and include the
importance of daily compliance for the control and management
of central precocious puberty and appropriate evaluation to
demonstrate this suppression.

The adverse experiences are primarily limited to injection site
reactions and vaginal bleeds probably because of withdrawal of
estrogen. These are not totally unexpected although the patients
or parents should be aware of these problems. There is still a
question whether label should read 28 days or 
dosing. I believe it should say 28 days since there are
inadequate data to support a longer interval.



13 Recommendations

This NDA is approvable. The sponsor must be committed to the long-
term follow up of all central precocious puberty patients treated, and
this should be a condition of approval. It will be important to
evaluate reproductive function in these patients after they become
adults. Final adult heights should be measured so that the -
effectiveness of this therapy in facilitating normal development can
be fully assessed. It is important also to note whether these girls 34

 

 

a?



 



 

have an increase in ovarian which have been described only in
.mecdotal reports with other analogs. The 32 children included
in the depot trial 90-5 16 should be monitored throughout their
resumed puberty and over their reproductive years.

Although the sponsor has provided data to suggest that patients can
be treated at 30 days rather than 28 days I would encourage the
sponsor to continue stating in the label that the depot be given every
4 weeks. In 90-5 16 study 114 doses were given within 29 days. In
the remaining children injected at longer periods, as long as 39 days,
it is unclear whether adequate suppression of gonadal function was

achieved.

The early diagnosis and effective treatment of central precocious
puberty is very important not only for promoting normal physical
development of these children but for restoring their 
well-being. It is essential that the pediatric endocrinologists who
utilize analog therapy for this condition understand the
importance of rapid and sustained suppression of the gonadal axis to
the achievement of these clinical objectives.



. 


Jean L. Fourcroy, M.D.

Chledical Of?cer
?Kalahari .
NDA 20-263
HFD-3 40 MM
HFD-S 10 -

10/]Fourcroy/January S, 1993

. \\t\q5

35

 

 

 H. 

   


APPENDIX.
REFERENCES
LIST OF INVESTIGATORS 90-053 
DOSAGE-B OF LEUPROLIDE 1N YOUNGEST TREATED CHILDREN 
I DOSES AND FORMULATIONS.

STUDY SCHEME 90-5 16

FIGURES FROM SUBMISSION
ESTRADIOL
TESTOSIERONE
GROWTH RATE
DELTA CA

TANNER STAGES

 

.. - .n?n?vW-wup-n-r?ww' 

References 

Bayley and Pinneau,S. Tables for predicting adult height from
skeletal age; revised for use with Greulich-Pyle Hand Standards. J.
Pediatrics 40:432?41, 1952.

Camacho, A, aet a1. Alterations of testicular histology and
chromosomes in patients with constitutional sexual precocity treated
with medroxyprogresterone acetate. GEM: 34:279-286, 1972.

(This article notes the histological aberations with
Medroxyprogesterone acetate).

Boepple et al. Use of a potent, long acting agonist or gonadotropin-

releasing hormone in the treatment of precocious puberty. Endo Rev.



Cook JS, Doty KI, Conn PM, and Hansen JR. Asessment of depot
leuprolide acetate dose- adequacy for central precocious puberty.
JCEM 74:1206-1209, 1992.

Jolly H. Sexual Precocity. Charles C. Thomas, Spring?eld, I1 1955.

Kalplan S. Idiopathic isosexual precocity therapy with
medroxyprOgresterone. Am J. Dis Child: 1 16:591.1968.

Kappy M, Stuart T, Perelman A et Suppression of gonadotropin
secretion by a long-acting gonadotropin?releasing hormone analog
(leuprolide acetate, LUPRON Depot) in children with precocious
puberty. Clin Endo Metabol 69::1087?1089. 1989.

Lee P. Medroxyprogesterone therapy for sexual precocity in girls.
Am]. Dis Child 135: 443-445, 1981. 3

Lee and Page J. Effects of leuprolide in the treatment of central
precocious puberty. J. Pediatrics . 321?324,1989.

MacLoed,TL et a1 . Anaphylactic reaction to luteinizing
hormone-releasing hormone. Fert Sterility 48:500, 1987. (Factrel)

Parker K, Lee P. Depot leuprolide acetate for treatment of precocious
puberty. Clin Endo Metab 69:689?691, 1989

 

 

Pescovit2,O Comite et a1 . The NIH experience with precocious
puberty. Joumal of Pediatrics. January 1986.

Styne, and Grumbach M. Puberty in the Male and Female. Chapter

from Reproductive Endocrinology, 2nd Edition Yen and affe. W.B.
Saunders 1986.

Tanner, .M. et al Clinical Longitudinal standards for height and
height velocity for North American Children. J. Pediatn?cs 107:3 17-
329,1985. One of the standards of growth use in all studies iwth
children with precocious puberty. .

Thamdrup E. Precocious Sexual Development. A Clinical Study of
100 children. Charles C. Thomas, Spring?eld, I1 1961.

Werder EA et al Treatment of precocious puberty with cyproterone
acetate. Pediatr Res 

Common Abbreviations used

CPP Central precocious puberty

FSH Follicle stimulating hormone

LH Luteinizing hormone

Luteinizing hormone releasing analog
LRF - Luteinizing Releasing Factor

 

 

 

INVESTIGATORS FOR STUDY 90-053
No.

Barry Bercu, 
University of South Florida College of Medicine
St. Petersburg, FL 33701

Robert M. Blizzard, M.D.3 1,854
University of Virginia Children's Medical Center
Charlottesville, VA 22908

Clifford A. Bloch, 
The Children's Hospital
Denver, CO 80218-1088

Michael J. Bourgeois, 
Texas Tech University Health Sciences Center
Lubbock, Texas 79430

Salvador Castells, 
State University of New York Health Science Center at Brooklyn
Brooklyn, NY 11203

Stuart A. Chalew, 
University of Maryland
Baltimore, MD 21201

Matthew H. Connors, 
Univeristy of California Davis Medical Center
Sacramento, CA 95817

Raphael David, 
NYU Medical Center
New York, NY 10016

lawrence Dolan, 
Children's HOSpital Medical Center
Cincinnati, OH 45229

Andrea Eberle, M.D., 
Univeristy of Tennessee Medical Center
Knoxville, TN 37920 

 

 

 

Ilene Fennoy, 
Columbia University
New York, NY 10037

Luigi Garibaldi, 

Cardinal Glennon Children's Hospital
St. Louis, MO 63104

Mitchell E. Geffner, 
University of California at Los Angeles
Los Angeles, CA 90024

Lillian Gonzalez de Pijem3 1,447
Universio?vd de Puerto Rico
San. Juan, PR 00936

Nancy (3-. Greger, M.D.3 1,477
University of Nebraska Medical Center
Omaha, NB 68105-1065

Jerome A. Grunt, M.D., 27,637
The Children's Mercy Hospital
Kansas City, MO 64108

Raymond Hintz, 
Stanford University Medical. Center
Stanford, CA 94305

James M. Horner, 
Medical College of Ohio
Toledo, OH 43 699-0008

Selna Kaplan, M.D., 5
University of California at San Francisco
San Francisco, CA 94143

Michael Kappy, 
St. Joseph's Hospital Children's Health Center
Phoenix, AZ 85001?2071

Lyndon Key, 1

.. ..

gal 

 

 

Wake Forest University, Bowman Gray School of Medicine

Winston-Salem, NC

 

Peter A. Lee, 

University of Pittsburgh Children's Hospital

Pittsburgh, PA 15 2 1 3

Penny Manasco, 36,065

National Institute of Environmean Health Science

Chapel Hill, NC 27599-7220

David K. McGowen, 
St. Joseph's Hospital and Medical Center
Tacoma, WA 98405

Robert McVie, M.D.5 2,253
Louisiana State University Medical Center
Shreveport, 1A 7 1 130

George M. Moll, M.D., 911327593

The University of Mississippi Medical Center

Jackson, MS 39216-4506

Wayne V. Moore, 

University of Kansas College of Health Sciences

Kansas City, KS 66103

Antoinette Moran, 
University of Minnesota
Minneapolis, MN 55455

John S. Parks, M.D.Z 7,828
Emory University School of Medicine
Atlanta, GA 30322

Alvin Perelman, 
Phoenix Children's Hospital
Phoenix, AZ 85006

Ora Pescovitz, 
Riley Children's Hospital
Indianapolis, IN 4-6223



Leslie Plotnick, 
Johns HOpkins Children's Center
Baltimore, MD. 21205

r, ?gen-#15. may a -. 
. -- ?lantern/"erases? ..

-

 

 

I.

Men?ily Poth, 
Uniformed Services University School of Medicine
Bethesda, MD. 20014

Geoffrey Redmond, 
Beachwood, OH 44122

Susan Rose, 
University of New Mexico
Albuquerque, NM 8713 1

Robert P. Schwartz, 1
Charlotte, NC 2823 2-2861

Neil H. White, 
Washington University School of Medicine
St. Louis, MO 63110

William B. Zipf, 
Ohio State University Children's Hospital
Columbus, OH 43 205

 

TABLE 4

DOSAGES OF LUEPROLIDE ACETATE FOR
TREATED CHILDREN

Age at Start of Therapy Final Depot Dose
Study Patient Number (yrs) (meg/kg)
P90-053 Blizzard 8 0.8 743
1.2 244
Dolan 3 3.0 397
Dolan 4 2.8 503
Dolan 7 1.7 591
1 2.2 765
Eberlc 3 l. 1 5 l7
4 1.2 503
Garibaldi 2.8 347
Garibaldi 7 2.4 342
Grunt 3 2.7 539
Kaplan 5 2.5 300
Kappy 16 2.9 536
Kappy 1.4 625
McCowcn 1 1.5 789
Pescovitz 8 2.0 200
Pcscovitz 13 2.9 200
Zipf 1 2.2 242
M90516 1.1 909 1.1 1027

 

r" 

 



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13-16
16 r?

 

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Lupron

Depot?

Protocol No. 
Page l0

TIME.
twin

Baseline

weeks
4 6m?
II no

end '0fo

6.3 Study Schematic

The following procedures or tests will be performed at the speci?c visits.

HT. WT. beam isle Hemuhugy/ Ultrnunuul
PE. Tatum BONE AGE Gull}! Acetntc Clittinl Butte
Staging I a (1) T431 (3) TEST Lord: Chemistry Demity 















- 

1.

Height should be measured in the morning using standand

. stadiometty equipment and, if possible, by the same person

at each visit; Tanner staging should also be rated by the same
pence if possible.


All ?lms to be read centrally at the Fels Institute using the Fels
Method. 

Sample drawn at -20 or 0' and 90 minutes {during 
stimulation test).

Standard method using Factrel [00 meg (IV bolus). Samples .

will be drawn minutes. Testing
should be done in the morning if possible.

Retest at week 8 if LH values from stimulation test
exceed [.75 at week 4.

6. To be done at selected sites.

h'mh'? t-l
L?lf?f??tlc
Atrial: It 1
01.151
Suspemimi

OI
0








ran ptti-x .. 

FIGURE 2.TANNER STAGES - MALES

Physical changes during Idolescence are important events. These Chan
some boys and not until nearly 14 tor others. It usuelly takes about to
are some drawings that show the dunges in penis. testes and pubic
most closely. Your doctor will review these with you.

 

Look only at pubic hair in these

pictures. Circle the picture that
most closely matches your pubic
hair. ll you have no hair around
your penis. circle picture 1. ll pubic
hair has just started to grow. circle
picture 2. If your pubic hair looks
like an adult man's. circle picture 5.

 

 



 

 

 

 

 

gee start at di?erent ages. a: early as 9 [or
Ht
hair. Please circle the picture that matches yt

look at penis and testes size in these pictures. Circle the
picture that most closely matches your development.

1 

 

 

 

 

 

 

. Penis and testes have a

3M begun to enlarge

. The testes have enlarge:

a little bit

. Testicle: are a little

lar'ec huts has grown

. Testicle-.1 grow a little

more. Peril! continues to

you towerd adult size

. Penis Ind are

adult six!



113..



. m?mm?n?n'm?u .. . .

1. .
.wW-hwhl?-H?W "hr- ?9

 

FIGURE 3.TANNER STAGES - FEMALES

Physical changes during adolescence are important events. These changes start at different ages.
some girls and not until nearly 13 for others. It usually takes about tour years from the first chan
Please circle the picture that most closely matches your breast. and pubic hair devel0pment. You

these with you.

 

 

 

Look at the pubic hair in these
pictures. Circle the picture that
most closely matches your pubic
hair. If you have no pubic hair.
circle picture I. If pubic hair just
started to grow. circle picture 2. If
pubic hair looks like an adult
female's. circle picture 5.

 

 

I 
.2 
\h 


 

 

 

 

Look at breast size in these pictures. Circle the picture
that most closely matches your breast development.


)1
2 


as early as 8 for
ges to the last.
dOCIor Will review

. There is

no breast
enlargement

. Breasts have

iust begun to
grow under.
need: the
nipple

Breast tissue
is larger

. Breast deveiop.

ment continues

. Breasts look

like an adult's

 

. 

 



 

Flgure 4. ESTRADIOL

 

 

 

I STYNE1
Cl comma
I 990-053
. I MSG-516.

 

 

 

?rear. AI

 



Figure 5. TESTOSTERONE

 

 

 

48

(Months!

?907516




MONTHS
3 

 

Figure 6. GROWTH RATE

 

 

 

 

990-053
MOO-516
5mm
cowrsz


 

 

 

MONTHS
BASELINE
3Months on Therapy

990-053 ?(115.115.
w-zzShir-.- bid-r

. -.
wr- 4- Jar-J1 - gun-.33. 1w; 

 

 

 

 

 

 


i
i


Figure 305mm
1 Poo-053
0.3 
mac?513 
0MONTHS 990-053 
BASELINE ~=NDA 20263 (2 of 2)

 litmw?p? - - 

If



1.13
1.15
1.4
1.2

11
0.8
0.8
0.4 
0.2

MONTHS

12
24
36
48

Figure 8. A BAIA CA

1 2 24
Months

P90-053
71
64
31
1 1
7

log-2;. .5155.

 

 


BOEPPLE2
P90-053

 

 

36

48

man-Ll

.a?c'crm .. -.



 

 

Dh/

APR 3 ,992
4?2~92
NDA 20~263
TAP Pharmaceuticals Inc.
Deerfield. Illinois
simmaamm 2-14?92 2?19?92



Drug; Leuprolide acetate

Abbott?43818

Iherapeutio_indieation; Treatment of children with central precocious
puberty.

Enoposed_therapeutic?dgse; 0.3 mg/kg/month administered as a single
intramuscular injection. Minimum dose 7.5 mg and maximum dose 15.0 mg.

WW INDs

All the preclinical toxicology has been previous reviewed in the above
referred INDs and NDAs.

Comparing the effect of Leuprolide acetate as daily injection and as 
depot formulation in the adult and prepubertal rat, it was shown that
prepubertal rat is much less sensitive to the drug than the adult rat which
has also been reported in clinical practice. Comparing the results of
subchronic toxicity/reproduction study of Abbott?43818 (at dose of 20 and 200
ug/kg/day} and (at doses of 10 and 30 mg/kg/4 weeks of the
fC?mulation) in immature rate, it was reported that while both form of
treatment decreased reproductive organ weights, daily injection had decreased
testosterone leVels in males and had no effect on estradiol levels in females
and SR formulation had no effect on either testosterone or estradiol.
Following cessation of treatment, complete recovery of the atrophic sex and
accessary sex organs was reported in female rats but only partial in male
rats.

.anheiolloai nainanJuths-Liabelins need. 
Wands;

1- Under Clinical Pharmacology. it is stated that animal and human studies
indicate that following an initial stimulation, chronic administration of
leuprolide acetate results in suppression of ovarian and testicular

steroidogenesis. This statement is true for humans but no animal data has

been submitted to support this statement. In fact in the immature rats. depot
formulation administration had no significant effect on either testosterone in

 

I

4v 
a

 

males or estradiol in females even when given at 10X prOposed HTD. The said
statement should therefore. be either supported with data or reference to
animal studies be deleted. The sponsor has been requested today on phone to
submit reference to appropriate studies.

2. The multiples of the HTD given for the preclinical studies are based on
doses proposed for treatment of prostate cancer with 7-5 mg Lupron depot/month
which represents a dose of 150 ug/kg for a 50 kg person. Since the proposed
dose for treatment of precocious'miberty is higher (0.3 mg/kg/month), the
multiples of HTD should be accordingly corrected under Contraindications on
page 4 and Overdosage on page 7.

3- Under Carcinogenesis, Mutagenesis, Impairment of fertility at the"end of
second paragraph on page 6, after the sentence ?In both sexes, the 
of the treated animals appeared normal?, it should be stated that the effect
of the treatment of the parents on the reproductive performance of the F1
generation was not tested-

4. Under adverse reactions on page 7, it is stated for Body as a Whole, the
word hypertrophy. It should be clarified as to hypertrophy of which organ.

Recommendations: Review of the data submitted previously under various INDs
and NDAs for prostate carcinoma, uterine fibroids and endometriosis along with
preclinical and clinical information available for other analogs for
various indications, Pharmacology recommends approval of Leuprolide acetate
(Lupron injection, 5 mg/ml and Lupron depot injection 7.5, 11.25 and 15 mg)
for the treatment of children with central precocious puberty.

The sponsor should however, be requested to make necessary changes in the
Labeling section as indicated above.

KY/S/t?ut Res/Aye. i732!
Krishan L. Raheja, 

. a4

*1
Original NDA 20?263 -
rim-345 7/3 ?7 2..
HEB-510

HFD?SlO/Jordan
4-2-92, N20-263.ori

 

 

 

 

 

 

APR 2131993
DIVISION OF METABOLISM AND ENDOCRINE DRUG PRODUCTS .
Review of Chemistry, Manufacturing, and Controls 1
20-263 CHEM. REVIEH 3 REVIEW DATE: 3-18-93
SUBMISSION TYRE DOCUMENT DATE CDER ATE ASSIGN ATE
Original . 2-14-92 2-18-92 2?25?92 I
1 Resubmission 5?29-92 6?4-92 6-5?92 4
Amendment 3/31/93 4/5/93 4/12/93
NAME ADDRESS OF APPLICANT: TAP PHARMACEUTICALS INC.
Bannockburn Lake Office Plaza
2355 Haukegan Road
Deerfield, IL 60015
DRUG PRODUCT NAME:
Proprietary: Lupron Depot-PED"Vlupron Injection
Non-proorietarv/USAN: Leuprolide acetate for depot su5pension/
LeUprolide acetate Injection
ggde Name/Number: TAP-144-SR
Chem. TVDe/Ther. Class: 5 
NDA Suitability PetitionlDESI/Patent Status: 

 

PHARMAQQL. Gonadotropin releasing hormone 
agonist to be used for the treatment of central precocious puberty.

 

DOSAG Lyophilized micrOSphere powder to be
reconstituted with diluent/Aqueous solution
Depot (3.75 mg and 7.50 mg)/Injection
(5 mg/mL)
ROUTE OF ADMINSTRATION: Intramuscular injection
DISPENSED: Rx OTC



CHEMICAL FORMULA. MOLECULAR FORMULA. MOL. UT:

Leuprolide Acetate: 
acetate

SUPPORTING IND

NDA 19-010 (Lupron, TAP Pharmaceuticals Inc.)

NDA 19-732 [Lupron Depot (7.50 mg), TAP
Pharmaceuticals Inc.]

NDA 20-011 [Lupron Depot (3.75 mg), TAP
Pharmaceuticals Inc.]

RELATED DOCUMENTS:
CONSULTS:

 

39-263 TAP PHARMACEUTICALS INC. LUPRON DEPOT


1. The revised package inserts for Lupron Depot-FED? and Lupron Injection as
well as outer carton labels are included in the 3/31/93 amendment.

2. The major change is to replace word with "4 weeks" in the package
insert for Lupron Depot-FED.



The revised packaged inserts for Lupron Depot-PED'" and Lupron Injection as
well as outer carton labels are found to be acceptable. There is no pending
chemistry issue with this NDA.

cc:
Orig. NDA #20-263
HFD-5lO/Division File

HFD?SlO/CHaynard


P.

init. 
_/45 Chien-Hua Niu, 
717%} Review Chemist

if/z filename; Disc 

 

DIVISION OF METABOLISM AND ENDOCRINE DRUG PRODUCTS
Review of Chemistry, Manufacturing, and Controls

 

 

NDA 20-263 CHEM. REVIEN 2 3-18?93
SUBMISSION TYPE DOCUMENT DATE CDER DATE ASSIGNED DATE
Original 2-13?92 2-25-92
Resubmission 5-29?92 6-4-92 6?5-92

ADDRESS OF APPLICANT: TAP PHARMACEUTICALS INC.

 

Bannockburn Lake Office Plaza
2355 Uaukegan Road
Deerfield, IL 50015

DRUG PRODUCT NAME:

 

 

Propri etarx: Lupron Depot - Lupron Inject i on
Non-proprietargZUSAN; Leuprolide acetate for depot suspension/
LeUprolide acetate Injection
Code NameZNumber: TAP-144, 
Chem. TxpelTher. Class; 5 5
DNA Status: 

 

PHARMACOL. CATEGORYZINDICATION: Gonadotropin releasing hormone 
agonist to be used for the treatment of central precocious puberty.

DOSAGE FORM: Lyophilized microsphere powder to te
reconstitute with diluent/Aqueous solution
Depot (3.75 mg and 7.50 mg)/Injection'
(5 "lg/ml)
ROUTE 0F ADMINSTRATION: Intramuscular injection
DISPENSED: Rx OTC

CHEMICAL NAME. STRUCTURAL FORMULA. MOLECULAR FORMULA: WOL. NT:

Leuprolide Acetate: 
acetate

IND
NDA 19-010 (Lupron, TAP Pharmaceuticals Inc.)

NDA 19-732 [Lupron Depot (7.50 mg). TAP
Pharmaceuticals Inc.]

NDA 20-011 [Lupron Depot (3.75 mg), TAP
Pharmaceuticals Inc.]

RELATED DOCUMENTS:
CONSULTS:

1w 



 

ant--

20-263 TAP PHARMACEQTICALS INC. LUPRON DEPOT




1. The fine inspection of Shonar Plant, Takeda Chemical Industries,
Japan, and Abbott Laboratories, USA, is acceptable to the Office of Compliance

(see the attached).

CONCLUSIONS RECOMMENDATIONS:
compliance status of facilities have been evaluated and found to be
acceptable. Therefore, the drug is approvable from chemistry viewpoint.

CC:
0 NDA #20-263

F1

3

HFD-510;CHaynard 

urn-510 YYChiu - 
R/Dinit. by: -4 

4 
5gb ?Chien-Hua Niu, 
07?! Review Chemist
\x

filename: Disc 

 

 

 

FEB ?xx;

DIVISION OF METABOLISM AND ENDOCRINE DRUG PRODUCTS
Review of.Shemistry, Manufacturing, and ControTs

 

 

 

 

NDA 20-263 CHEM. REVIEN 1 2-2-93'

SUBMISSION TYPE DOCUMENT DATE CDER DATE ASSIGNED DATE

Original 2-14-92 2?18-92 2-25-92

Resubmission 5-29-92 6?4-92 6-5-92

AMENDMENT 7-14-92 7-16-92 7-15-92
8?24-92 8-31-92 9-1-92
11/23/92 11/25/92 12/31/92
12-17-92 12-21-92 12-21-92
1?6?93 1-7-92 1-15-92
1-29-93 1-29-93 2-2-93

NAME ADDRESS OF APPLICANT: TAP PHARMACEUTICALS INC.

 

Bannockburn Lake Office Plaza
2355 Naukegan Road
Deerfier, IL 60015

DRUG PRODUCT 

 

 

 

 

Proprietary: Lupron Depot- Injection
Non?propriei LeuproTide acetate for depot suspension/
LeuproIide acetate Injection
Code Name/Number: TAP-144, 
Chem. Txpe/Ther. CTass: 5 
DNA Suitability Petition/DESI/Patent Status: 

 

PHARMACOL. Gonadotropin reTeasing hormone 
agonist to be used for the treatment of centraT precocious puberty.

 

DOSAGE FORM: LyophiTized microsphere powder to be
reconstitute with diluent/Aqueous solution
Depot (3.75 mg and 7.50 mg)/Injection
(5 m9/mL)
ROUTE 0F ADMINSTRATION: IntramuscuTar injection
Rx OTC

CHEMICAL NAME, STRUCTURAL MOLECULAR FORMULA, MOL. NT:

LeuproTide Acetate: 
acetate

SUPPORTING DOCUMENTS: IND 

NDA 19-010 (Lupron, TAP Pharmaceuticals Inc.)

NDA 19-732 [Lupron Depot (7.50 mg), TAP
Pharmaceuticais Inc.]

NDA 20-011 [Lupron Depot (3.75 mg), TAP
Pharmaceuticais Inc.] .

 

 

CONCLUSIONS RECOMMENDATIONS: 
Because both Lapron Injection and Lupron Depot dosage forms (3.75 mg and 7.5
mg) used for the new indication (central precocious puberty) have previously
been approved for NBA #19-010, NDA #20-011 and NBA #19,?32, respectively,
there is no outstanding issue with respect to chemistry, manufacturing and
controls of the drug products. In addition, compliance status of
facilities have been evaluated and found to be acceptable. Therefore, the
drug is approvable from chemistry viewpoint.

cc:
Orig. NDA #20-263

HFD?SlO/Division File


HfD-SlO/CMaynard 
47
HFD?lOZ/CKumkumian . _5n
init. by: Chien-Hua Niu, 
Review Chemist
f/y/i? filena_m_e_; Disc 

 
 



 

 

1"

230m 1992 

LUPRON ACETATE TAP PHARMACEUTICALS
NDA 20-263 Deerfield, IL

Reviewer: K. Daniel Gordin, Submission Date
May 29, 1992
July 28, 1992


OCT 2 6 '992


The Division of Biopharmaceutics has reviewed the Biopharmaceutics
data submitted for Lupron Acetate submitted on May 29, 1992 and
found it acceptable.

Please convey the Labeling Comments to the Reviewing Medical
Officer and if appropriate to the sponsor.

I 

M. Daniel Gordin, 
Pharmacokinetics Evaluation Branch



cc: NDA 20-263, RFD-510, Hrs?510 (FourcroY): RFD-426 (Gordin and
Fleischer), Drug, Chron, Reviewer, and RFD-19 (F01).

 

Initialed by Nicholas Fleischer, 

 



 

 



Drug:

Dosage Forms:

Indication:

Action:

Dosing:

Chemistry:

Leuprolide acetate is a nonapeptide
analog of naturally occurring gondatropin releasing
hormone.

3.75 mg and 7.5 mg Lupron Depot
Lupron Injection

New Indication for treatment of children with
neutral precocious puberty. Both Lupron Depot and
Lupron Injection have been approved for prostate
cancer in 1989 and for endometriosis in 1990.

By the inhibition of and suppression of ovarian and
testicular steroidogenesis.

Recommendation in the package insert for 
DEPOT is as follows: The starting dose to be
administered by the child's weight:

?25 kg - 7.5 mg
>25?37.5 kg 11.25 mg
>37.5 kg 15 mg

For Lupron Depot the recommended starting dose is
0.3 mg/kg (min 7.5 mg) administered as a single In
injection.. If total downward regulation of
hormones is not achieved, then the dose should be
titrated upward in increments of 3.75 mg/month to a
max of 15 mg/month which will be considered the
maintenance dose. 

For Lupron Injection, the recommended starting?dose
is 0.3 mg/kg subcutaneous daily injection.

Leuprolide is a nonapeptide. The chemical
name 

rolinamide acetate

The sponsnr was requested to submit any bio-data they had from a
pediatric pepulation. One study was submitted which will be

reviewed.

 

 

. 

PLASMA CONCENTRATIONS OF CHILDREN IN THE
TREATMENT OF PRECOCIOUS PUBERTY (PROTOCOL M90r516)

Dr. Raymond Hintz; Stanford U. Medical Center


This was a 9 site study involving 22 patients (age 1.1 to 8.9
years; weight 13.1 to 51.5 kg; 2 20 F) who received Lupron Depot
at doses of 7.5 mg, 11.25 mg, and 15 mg based on weight category at
intervals of once 4 weeks for 6 doses. Blood samples were
obtained on Week 4, 12, and 24 before injection. The leuprolide
plasma concentrations were analyzed by a validated RIA assay which
was sensitive down to 0.1 ng/ml and shown to be 87.4 to 99.8%
percent accurate for the quality control standards.



Table 1. The individual drug conc at weeks 4, 12, and 24 by dose.-

Eiikgl ?k_i 12 21
7.5 mg 27.0 .4 .4 .8
22.2 .7 .5 .5
21.4 .7 .9 1.1
2912 _15_ ?ii. 118
Mean 22.7 .56 .55 .80
11.25 mg 36.8 .8 .8 .9
36.4 .3 .9 .5
34.3 .5 1.1 1.8
32.4' 2.8 2.3 1.2
31.8 .5 .3 1.7
30.1 1.2 1.2 1.5
29.9 .9 1.2 1.5
2511 219 111 112
Mean 32.5 1.2 1.1 
15.0 mg 51.5 1.3 .4 .7
48.0 1.3 2.2 .8
47.9 1.2 1.9 1.1
42.9 1.2
42.4 2.3 1.6 1.4
42.2 2.3 2.2 2.5
39.6 2.1 1.4 2.1
2211 .15 ail _12
Mean 44.2 1.5 1.6 1.2

1. The study results show 1) a trend of increasing drug

concentration with increasing dose and 2) relatively consistent
trough plasma concentration on Weeks 4, 12, and 24 which appears
that the pre-dosed leuprolide plasma concentrations are sustained
free trough to trough (Table 1). -



 

2. The doses on a mg/kg basis range from the minimum of 0.3 mg/kg
to 0.45 mg/kg as follows:

7.50 mg 0.3 mg/kg

11.24 mg 0.45 0.4 mg/kg

15.00 mg 0;4 mg/kg

The sponsor was asked in a Teleconference on October 19, 1992, the
following questions concerning the dose and dosing recommendation:

1) The starting dose as recommended in the labeling is divided
into 3 doses based on 3 weight categories as opposed to
administering on a /kg body weight basis. Is there a problem with
subtherapeutic and/or toxic doses. What is the rationale for this
recommendation?

They responded that since they have 3.75 mg and 7.5 mg fixed
dose vials, it is easier to administer Lupron depot without
splitting doses. The minimum starting dose is 0.3 mg/kg (7.5
mg). Depending upon patient's response as measured by 
stimulation test, sex steroids, and Tanner staging to confirm
down regulation, the.dose is titrated upwards in increments of
3.75 mg/month to a maximum of 15 mg/month. Slight overdosing
is not-a concern since there is a lack of toxicity associated
with leuprolide. (This was verified with the Agency's
Reviewing Pharmacologist.) 

2) Is the patient's dose increased as they mature and body weight
increases?

They have found that once a patient is downregulated, the dose
does not require upward adjustment, and the patient can be
maintained at that dose until therapy is stopped. Also, a
tapering of the dose is not needed when therapy is stopped.

3) Was the injection site varied in the clinical studies?

The injection site is most commonly in the buttock. The
injection site ?was varied in the clinical studies with
patients' response not changing.

4) What was the maximum injection volume used, and what were the
results?
The maximum injection volume used was 2 mL, and patientsII
stayed downregulated. -

5) Is the once~a-day Lupron suspension injection to be marketed?

It will _be marketed even though they realize there is no
rationale for it because of the availability of the once-a-
month Lupron depot; however, because there are
Endocrinologists who still request it, they will continue to
market it. 

 


The following statements are suggested for the labeling.

1. There is approved labeling for both products. However, in the
proposed labeling in the new indication, the sponsor has combined
the details of Lupron Depot and Lupron Injection into one package
insert. Since these two products will be packaged separately and
since they already have approved package inserts, they should be
encouraged to split the two and have one insert for Lupron Depot
and one. for Lupron Injection. Any kinetic description of either
product should include the fact that it was obtained from adult
populations. However, for Lupron Injection, since PK data was not
submitted by the sponsor for this product in a pediatric
population, the following is suggested:

"The determination of leuprolide kinetics in a pediatric
population from the Lupron Injection was not done."

2. The following 'statement is suggested ?under the CliniCal
Pharmacology section on page 2 for the Lupron Depot package insert
based on the results of the precocious clinical study.

"In a precocious puberty clinical. study, 22 children (ages 1.1
to 8. 9 years; weight 13.1 to 51.23 kg; 2 males and 20 females)
received Lupron Depot at doses depending on weight at intervals of 1 injection every 4 weeks
for 6 total doses. Pre?dosed blood samples were obtained on
Weeks 4, 12, and 24. The mean (180) trough?leuprolide plasma
concentrations on Week 4 for the 7.5, 11.25, and 15 mg doses
were 0.77 (0.33), 1.25 (1.06), and 1.59 (0.65) ng/mL,
respectively. Levels were relatively consistent on Weeks 12
and 24." I

3. The following should be added to 

sections.

"0nce a patient is downregulated, the dose does not require
upward adjustment, and the patient can be maintained at that
dose until therapy is stopped."

- ?an:

11?.

 

No. 3639, 3629
LUPRON DEPOT 3.75 mg and 7.5 mg
(leuprolide acetate for depot suspension)

No. 36126? 
LUPRON 
(leuprolide acetate) Injection

DESCRIPTION 
Leuprolide acetate is a nonapeptide analog of naturally occurring gondatropin 
releasing hormone or The analog possesses greater potency than the

natural hormone. The chemical name is

N-ethyl-L?prolinamide acetate (salt) with the following structural formulaOH. 
J-c?u-cuacCH, CH: CH: Cl": 
cl.? d] cth? clu on. - on (in,
a 
on 
o=un
in.

 

LUPRON DEPOT is supplied in two Each vial contains sterile lyophilized
microspheres, which when mixed with diluent, become a suspension, which is intended as a
intramuscular injection.

- The single-dose vial of LUPRON DEPOT contains leuprolide acetate
(3.75/7.5 mg), puri?ed gelatin (0.65! 1.3 mg), DL-lactic glycolic acids
copolymer mg), and D?mannitol (6.6/132 mg). The accompanying
ampule of diluent contains sodium (7.5 mg),
D-mannitol (7'5 mg), polysorbate 80 (1.5 mg), water for injection, USP, and
acetic acid, NF to control pH.

LUPRON Injection is a sterile, aqueous solution intended for daily subcutaneous injection.

0 A 2.8 mL multiple dose vial contains leuprolide acetate (5 mg/mL), sodium
chloride (6.3 mgme) for tonicity adjustment, benzyl?alcohol as a preservative
(9 mg/mL), and water for injection. The pH may have been adjusted with
sodium hydroxide and/or acetic acid.

 

CLINICAL PHARIVIACOLOGY

Leuprolide acetate, 3 agonist, acts as a potent inhibitor of gonadotmpin secretion
when given continuously and in therapeutic doses. Animal and human studies indicate that
following an initial stimulation, chronic administration of leuprolide acetate results in
suppression of ovarian and testicular steroidogenesis. This effect is reversible on
discontinuation of drug therapy.

Leuprolide acetate is not active when given orally. Bioavailability by subcutaneous
administration is comparable to that by intravenous administration. Leuprolide acetate has
a plasma half?life of approximately three hours. The metabolism, distribution and
excretion of leuprolide acetate in man have not been determined.

In children with central precocious puberty (CPP), stimulated and basal gonadotropins are
reduced to prepubertal levels. Testosterone and estradiol are reduced to prepubertal levels
in males and females respectively. Reduction of gonadotropins will allow for normal
physical and growth and deveIOpment. NatUral maturation occurs when
gonadotropins return to pubertal levels following discontinuation of leuprolide acetate.

The following physiologic effects have been noted with the chronic administration of
leuprolide acetate in this patient population.

1. Skeletal Growth. A measurable increase in body length can be noted since the
epiphyseal plates will not close prematurely. -

2. Qrgan Growth. Reproductive organs will return to a prepubertal state.

3. Menses. Menses, if present, will cease.

INDICATIONS AND USAGE

LUPRON DEPOT and LUPRON Injection are indicated in the treatment of children

with central precocious puberty. Children should be selected using the following criteria:

1. Clinical diagnosis of CPP (idiopathic or neurogenic) with onset of secondary sexual
characteristics earlier than 8 years in females and 9 years in males.

2. Clinical diagnosis should be con?rmed prior to initiation of therapy

0 Con?rmation of diagnosis by a pubertal response to a stimulation test.

The sensitivity and methodology of this assay must be understood.

0 Bone age advanced one year beyond the chronological age.

 

3. Baseline evaluation should also include
0 Height and weight measurements.
0 Sex steroid levels.
0 Adrenal steroid level to exclude congenital adrenal hyperplasia. 
0 Beta human chorionic gondotropin level to rule out a chorionic gonadotropin

secreting tumor,

4? Pelvic/adrenaJ/testicular ultrasound to rule out a steroid secreting tumor.
0 Computerized tomography of the head to rule out intracranial tumor.
CONTRAINDICATIONS

LUPRON DEPOT is contraindicated in women who are or may become pregnant while
receiving the drug. When administered on day 6 of pregnancy at test dosages of 0.00024,
0.0024, and 0.024 mg/kg (1/600 to 1/6 the human dose) to rabbits, LUPRON DEPOT
produced a dose related increase in major fetal abnormalities. Similar studies in rats failed
to demonstrate an increase in fetal malformations. There was increased fetal mortality and
decreased fetal weights with the two higher doses of LUPRON DEPOT in rabbits and with
the highest dose in rats. The effects on fetal mortality are logical consequences of the
alterations in hormonal levels brought about by this drug. Therefore, the possibility exists
that spontaneous abortion may occur if the drug is administered during pregnancy.

Leuprolide acetate is contraindicated in children demonstrating hypersensitivity to 
agonist analogs, or any of the excipients.

A report of an anaphylactic reaction to (Factrel) has been reported in the
medical literature.?

WARNINGS

During the early phase of therapy, gonadotropins and sex steroids rise above baseline
because of the natural stimulatory effect of the drug. Therefore, an increase in clinical
signs and may be observed (see "Clinical Pharmacology? section).

Noncompliance with drug regimen or inadequate dosing may result in inadequate control of
the pubertal process. The consequences of poor control include the return of pubertal signs
such as breast development, and growth. The long-term consequences of
inadequate control of gonadal steroid semeuon are unknown, but may include a further
compromise of adult stature.

 



 

PRECAUTIONS
Patients with known allergies to benzyl alcohol, an ingredient of the vehicle of Lupron

Injection, may present of hypersensitivity, usually local, in the form of
erythema and induration at the injection site.

Laboratory Tests: Response to leuprolide acetate should be monitored 1-2 months after the
start of therapy with a stimulation test and sex steroid levels. Measure-me? of bone
age for advancement should be done every 6-12 months.

Sex steroids may increase or rise above prepubertal levels if the dose is inadequate (see
section). Once a therapeutic dose has been established, gonadotropin at;
sex steroid levels will decline to prepubertal levels.

Drug Interactions: No pharmacokinetic-based drug-drug interaction studies have been
conducted. However, because leuprolide acetate is a peptide that is primarily degraded by
peptidase and not by cytochrome P-450 enzymes as noted in speci?c studies, and the drug
is only about 46% bound to plasma proteins, drug interactions would not be expected to

occur.

Dmg/Laboratory Test Interactions: Administration of leuprolide acetate in therapeutic
doses results in suppression of the pituitary-gonadal system. Normal function is usually
restored within 4 to 12 weeks after treatment is discontinued.

Infonnation for Parents: Prior to starting therapy with LUPRON DEPOT or
LUPRON Injection, the parent or guardian must be aware of the importance of continuous
therapy. Adherence to or daily drug administration schedules must be accepted if

therapy is to be successful.

it During the ?rst 2 months of therapy, a female may experience menses or

spotting. If bleeding continues beyond the second month, notify the physician.

Any irritation at the injection site should be reported to the physician
immediately.
0 Report any unusual signs or to the physician.

Carcinogenesis, Mutagcnesis, Impairment of Fertility: A two-year carcinogenicity study
was conducted in rats and mice. In rats, a dose-related increase of benign pituitary
hyperplasia and benign pituitary adenomas was noted at 24 months when the drug was
administered subcutaneously at high daily doses (0.6 to 4 mg/kg). There was a signi?cant
but not dose-related increase of pancreatic islet?cell adenomas in females and of testes
interstitial cell adenomas 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

 

.Jt?

u?A-r Unit 

 

high. as 60 mg/kg for two years. Adult patients have been treated with leuprolide acetate
for up to three years with doses as high as 10 rug/day and for two years with doses as high
as :10 mg/day without demonstrable pituitary abnormalities.

Although no clinical studies have been completed in children to assess the full reversibility
of fertility suppression, animal studies (prepubertal and adult rats and monkeys) with
leuprolide acetate and other analogs have shown functional recovery. However,
following a study with leuprolide acetate, immature male rats demonstrated tubular
degeneration in the testes even after a recovery period. In spite of the failure to recover
histologically, the treated males proved to be as fertile as the controls. Also, no histologic
changes were observed in the female rats following the same protocol. In both sexes, the
of the treated animals appeared normal. The clinical signi?cance of these
findings is unknown.

Pregnancy Category X. See section.

Nursing Mothers: It is not known whether leuprolide acetate is excreted in human milk.
LUPRON should not be used by nursing mothers.

ADVERSE REACTIONS
Potential exacerbation of signs and during the ?rst few weeks of treatment (See
section) is a concern in patients with rapidly advancing central

precocious puberty.

In two studies of children with central precocious puberty, in 2% or more of the patients
receiving the drug, the following adverse reactions were reported to have a possible or
probable relationship to drug as ascribed by the treating physician. Reactions considered
not drug related are excluded.

Number of Patients

11 398 (Percent)
Body as a Whole

General Pain 7 (2)
Integumentary System

Acne/Seborrhea 7 . (2)

Injection Site Reactions Including Abscess 21 (5)

Rash Including Erythema Multiforme 8 (2)

Urogenital System
Vaginitis/Bleeding/Discharge 7 (2)

 


:3

 

 

 

In those same studies, the following adverse reactions were reported in less than 2% of the
patients.

Body as a Whole - Body Odor, Fever, Headache, Infection; Cardiovascular System 
Syncope, Vasodilation; Digestive System Gingivitis,

Nausea/Vomiting; Endocrine System Accelerated Sexual Maturity; Metabotic and
Nutritional Disorders - Peripheral Edema, Weight Gain; Nervous System Nervousness,
Personality Disorder, Somnolence, Emotional Lability; Respiratory System Epistaxis;
Integumentary System Alopecia, Skin Striae; Urogenital System - Cervix Disorder,
Gynecomastia/Breast Disorders, Urinary Incontinence.

See other package inserts for adverse events reported in other patient populations.

OVERDOSAGE

In rats, subcutaneous administration of 250 to 500 times the recommended human dose,
expressed on a per body weight basis, resulted in decreased activity, and local
irritation at the injection site. There is no evidence at present that there is a clinical
counterpart of this phenomenon. In early clinical trials using leuprolide acetate in adult
patients, doses as high as 20 mg/day for up to two years caused no adverse effects differing
from those observed with the 1 mg/day dose.

DOSAGE AND ADMINISTRATION
LUPRON DEPOT must be administered under the supervision of a physician.
LUPRON INJECTION can be administered by a patient/parent or health care professional.

The dose of leuprolide acetate must be individualized for each child. The dose is based on
a mg/kg ratio of drug to body weight.

For either dosage form, after 1-2 months of initiating therapy or changing doses, the child
must be monitored with a stimulation test, sex steroids, and Tanner staging to
con?rm downregulation. Measurements of bone age for advancement should be monitored
every 6-12 months. The dose should be titrated upward until no progression of the
condition is noted either clinically and/or by laboratory parameters.

As with other drugs administered by injection, the injection site should be varied

periodically. Mfg, ytwim ?Wot/L) 

Discontinuation of leuprolide acetate should be considered before age ll for females and .. 04,0694
age 12 for males?it! fit? Vii/?ew/7 WJ 6
(Lot? {Vi 9 if},
.. KC 
7 9 

 

 

 

 

 

LUPRON DEPOT
The recommended starting dose is 0.3 mg/kg (minimum 7.5 mg) administered as a single
intramuscular injection. The starting dose will be dictated by the child?s weight.

525 kg 7.5 mg
>25?37.5 kg 11.25 mg
>375 kg 15 mg

If total downregulation is not achieved, the dose should be titrated upward in increments of
3.75 mg per month to a maximum of 15 mg per month. This dose will be considered the
maintenance dose.

The lyophilized microspheres are to be reconstituted and administered as a single
intramuscular injection. in accord with the following directions:

1. Using a syringe with a 22 gauge needle, withdraw 1 ml. of diluent from the ampule,

and inject it into the vial. (Extra diluent is provided; any remaining should be
discarded.)
2. Shake well to thoroughly disperse particles to obtain a uniform suspension. The

suSpension will appear milky.

3. Withdraw the entire contents of the vial into the syringe and inject it at the time 'of
reconstitution.

Although the suspension has been shown to be stable for 24 hours following reconstitution,
since the product does not contain a preservative, the suspension should be discarded if not
used immediately.

LUPRON Injection

The recommended starting dose is 50 administered as a single subcutaneous
injection. If total downregulation is not achieved, the dose should be titrated upward by
10 mcg/kg/day to a maximum of 100 mcg/kg/day. This dose will be considered the
maintenance dose.

NOTE: As with other parenteral products, inspect container?s solution for discoloration
and particulate matter before each use.

 

 

 



 

HOW SUPPLIED
LUPRON DEPOT is available in two 

LUPRON DEPOT (NDC 0300-3639,, 3629-01) is available in a vial. containing
sterile lyophilized microsp?eres which is leuprolide acetate incorporated in a
biodegradable copolymer of lactic and glycolic acids. The single-dose vial of
LUPRON DEPOT contains leuprolide acetate (3.75/75 mg), puri?ed gelatin
(0.65/13 mg), DL-lactic and giycolic acids copolymer (Sill/66.2 mg), and
D-mannitol (6.6/13.2 mg). The accompanying ampule of diluent contains
sodium (7.5 mg), D-mannitol (75 mg), polysorbate 80
(1.5 mg), water for injeCLion, USP, and acetic acid NF. When mixed with 1
mL of diluent, LUPRON DEPOT is administered as a single 

injection.

The vial of LUPRON DEPOT and the ampule of diluent may be stored at
room temperature. Keep from freezing.

Use the syringes supplied in the LUPRON DEPOT kits. Any 22-gauge needle
may be used with LUPRON DEPOT.

LUPRON (leuprolide acetate) Injection is a sterile solution.

A 2.3 mL multiple dose vial (NDC 0300-3626-28) contains leuprolide acetate
(5 mg/mL), sodium chloride (6.3 mg/mL) for tonicity adjustment, benzyl
alcohol as a preservative (9 mg/mL), and water for injection. The pH may
have been adjusted with sodium hydroxide and/or acetic acid.

Refrigerate until dispensed. The drug may Stored unrefrigerated below 
Avoid freezing. Protect from light - store vial in carton until use.

Use the syringes supplied in the LUPRON Injection kit. Low dose insulin
syringes may be substituted for use with Lupron Injection. The volume of
drug for the dose will vary depending on the syringe used and the
concentration of drug.

Caution: Federal (U.S.A.) law prohibits dispensing without a prescription.



 
  

REFERENCE
1. Macbeod TL, et al. Anaphyiactic reaction to luteinizing hormone?releasing
hormone. Fggil Steril 1987 

U.S. Patent No. 4,005,063; 4,005,194; 4,652,441; 4,677,191; 4,728,721; 4,849,228;
4,917,893, and 4,954,298. 

TAP Pharmaceuticals Inc.

Deer?eld, IL 60015, U.S.A.

LUPRON DEPOT manufactured by Takoda Chemical Industries, Ltd. Osaka,
JAPAN 541

Lupron Injection manufactured by Abbott Laboratories, North Chicago, 11, 60064.

- Registered

Last revised: 7/92