Lupron (leuprolide acetate) Injection, Solution

[Abbott Laboratories]

Rx only

DESCRIPTION

Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin releasing

hormone (GnRH or LH-RH). The analog possesses greater potency than the natural hormone. The
chemical name is 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N-
ethyl-L-prolinamide acetate (salt) with the following structural formula:

LUPRON INJECTION is a sterile, aqueous solution intended for subcutaneous injection. It is available
in a 2.8 mL multiple-dose vial containing leuprolide acetate (5 mg/mL), sodium chloride, USP (6.3
mg/mL) for tonicity adjustment, benzyl alcohol, NF as a preservative (9 mg/mL), and water for
injection, USP. The pH may have been adjusted with sodium hydroxide, NF and/or acetic acid, NF.

CLINICAL PHARMACOLOGY

Leuprolide acetate, an LH-RH agonist, acts as a potent inhibitor of gonadotropin secretion when
given continuously and in therapeutic doses. Animal and human studies indicate that following an
initial stimulation of gonadotropins, chronic administration of leuprolide acetate results in suppression
of ovarian and testicular steroidogenesis. This effect is reversible upon discontinuation of drug
therapy. Administration of leuprolide acetate has resulted in inhibition of the growth of certain
hormone dependent tumors (prostatic tumors in Noble and Dunning male rats and DMBA-induced
mammary tumors in female rats) as well as atrophy of the reproductive organs.

In humans, subcutaneous administration of single daily doses of leuprolide acetate results in an initial
increase in circulating levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH),
leading to a transient increase in levels of the gonadal steroids (testosterone and dihydrotestosterone
in males, and estrone and estradiol in pre-menopausal females). However, continuous daily
administration of leuprolide acetate results in decreased levels of LH and FSH. In males, testosterone
is reduced to castrate levels. In pre-menopausal females, estrogens are reduced to post-menopausal
levels. These decreases occur within two to four weeks after initiation of treatment, and castrate

Reference ID: 2920484

levels of testosterone in prostatic cancer patients have been demonstrated for periods of up to five
years.

Leuprolide acetate is not active when given orally.

Pharmacokinetics

Absorption

Bioavailability by subcutaneous administration is comparable to that by intravenous administration.

Distribution

The mean steady-state volume of distribution of leuprolide following intravenous bolus administration
to healthy male volunteers was 27 L. In vitro binding to human plasma proteins ranged from 43% to
49%.

Metabolism

In healthy male volunteers, a 1 mg bolus of leuprolide administered intravenously revealed that the
mean systemic clearance was 7.6 L/h, with a terminal elimination half-life of approximately 3 hours
based on a two compartment model. In rats and dogs, administration of 14C-labeled leuprolide was
shown to be metabolized to smaller inactive peptides, a pentapeptide (Metabolite I), tripeptides
(Metabolites II and III) and a dipeptide (Metabolite IV). These fragments may be further catabolized.

The major metabolite (M-I) plasma concentrations measured in 5 prostate cancer patients reached
maximum concentration 2 to 6 hours after dosing and were approximately 6% of the peak parent drug
concentration. One week after dosing, mean plasma M-I concentrations were approximately 20% of
mean leuprolide concentrations.

Excretion

Following administration of LUPRON DEPOT 3.75 mg to 3 patients, less than 5% of the dose was
recovered as parent and M-I metabolite in the urine.

Special Populations

The pharmacokinetics of the drug in hepatically and renally impaired patients has not been
determined.

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

CLINICAL STUDIES

In a controlled study comparing LUPRON 1 mg/day given subcutaneously to DES (diethylstilbestrol),

3 mg/day, the survival rate for the two groups was comparable after two years of treatment. The
objective response to treatment was also similar for the two groups.

INDICATIONS AND USAGE

LUPRON INJECTION (leuprolide acetate) is indicated in the palliative treatment of advanced

prostatic cancer.

CONTRAINDICATIONS
1. LUPRON INJECTION is contraindicated in patients known to be hypersensitive to GnRH,
GnRH agonist analogs or any of the excipients in LUPRON INJECTION: Reports of
anaphylactic reactions to GnRH agonist analogs have been reported in the medical
literature.1,2
2. LUPRON is contraindicated in women who are or may become pregnant while receiving the
drug. LUPRON may cause fetal harm when administered to a pregnant woman. Therefore, the
possibility exists that spontaneous abortion may occur if the drug is administered during
pregnancy. If this drug is administered during pregnancy or if the patient becomes pregnant
while taking any formulation of LUPRON, the patient should be apprised of the potential
hazard to the fetus.

WARNINGS

Initially, LUPRON, like other LH-RH agonists, causes increases in serum levels of testosterone.
Transient worsening of symptoms, or the occurrence of additional signs and symptoms of prostate
cancer, may occasionally develop during the first few weeks of LUPRON treatment. A small number
of patients may experience a temporary increase in bone pain, which can be managed
symptomatically. As with other LH-RH agonists, isolated cases of ureteral obstruction and spinal cord
compression have been observed, which may contribute to paralysis with or without fatal
complications.
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Safe use of leuprolide acetate in pregnancy has not been established clinically. Before starting
treatment with LUPRON, pregnancy must be excluded (see CONTRAINDICATIONS section).

Periodic monitoring of serum testosterone and prostate-specific antigen (PSA) levels is

recommended, especially if the anticipated clinical or biochemical response to treatment has not been
achieved. It should be noted that results of testosterone determinations are dependent on assay
methodology. It is advisable to be aware of the type and precision of the assay methodology to make
appropriate clinical and therapeutic decisions.

PRECAUTIONS

Patients with metastatic vertebral lesions and/or with urinary tract obstruction should be closely
observed during the first few weeks of therapy (see WARNINGS and ADVERSE REACTIONS
sections).

Patients with known allergies to benzyl alcohol, an ingredient of the drug's vehicle, may present
symptoms of hypersensitivity, usually local, in the form of erythema and induration at the injection
site.

Information for Patients

See INFORMATION FOR PATIENTS which appears after the REFERENCE section.

Laboratory Tests

Response to leuprolide acetate should be monitored by measuring serum levels of testosterone and
prostate-specific antigen (PSA). In the majority of patients, testosterone levels increased above
baseline during the first week, declining thereafter to baseline levels or below by the end of the
second week of treatment. Castrate levels were reached within two to four weeks and once attained
were maintained for as long as drug administration continued.

Drug Interactions

See CLINICAL PHARMACOLOGY, Pharmacokinetics section.

Drug/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.
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Carcinogenesis, Mutagenesis, Impairment of Fertility

Two-year carcinogenicity studies were 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 significant but not
dose-related increase of pancreatic islet-cell adenomas in females and of testicular interstitial cell
adenomas in males (highest incidence in the low dose group). In mice no pituitary abnormalities were
observed at a dose as high as 60 mg/kg for two years. Patients have been treated with leuprolide
acetate for up to three years with doses as high as 10 mg/day and for two years with doses as high
as 20 mg/day without demonstrable pituitary abnormalities.

Mutagenicity studies have been performed with leuprolide acetate using bacterial and mammalian
systems. These studies provided no evidence of a mutagenic potential.

Clinical and pharmacologic studies in adults (≥ 18 years) with leuprolide acetate and similar analogs
have shown full reversibility of fertility suppression when the drug is discontinued after continuous
administration for periods of up to 24 weeks. However, no clinical studies have been conducted with
leuprolide acetate to assess the reversibility of fertility suppression.

Pregnancy

Teratogenic Effects

Pregnancy Category X

(see CONTRAINDICATIONS and WARNINGS sections)

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 produced a dose-related increase in major fetal
abnormalities. Similar studies in rats failed to demonstrate an increase in major fetal malformations
throughout gestation. There was increased fetal mortality and decreased fetal weights with the two
higher doses of LUPRON in rabbits and with the highest dose in rats. The effects on fetal mortality
are expected consequences of the alterations in hormonal levels brought about by this drug.

Nursing Mothers

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

Pediatric Use
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See labeling for LUPRON INJECTION for Pediatric Use for the safety and effectiveness in children
with central precocious puberty.

Geriatric Use

In the clinical trials for LUPRON INJECTION, the majority (69%) of subjects studied were at least 65
years of age. Therefore, the labeling reflects the pharmacokinetics, efficacy and safety of LUPRON in
this population.

ADVERSE REACTIONS

Clinical Trials

In the majority of patients testosterone levels increased above baseline during the first week,
declining thereafter to baseline levels or below by the end of the second week of treatment. This
transient increase was occasionally associated with a temporary worsening of signs and symptoms,
usually manifested by an increase in bone pain (see WARNINGS section). In a few cases a
temporary worsening of existing hematuria and urinary tract obstruction occurred during the first
week. Temporary weakness and paresthesia of the lower limbs have been reported in a few cases.

Potential exacerbations of signs and symptoms during the first few weeks of treatment is a concern in
patients with vertebral metastases and/or urinary obstruction which, if aggravated, may lead to
neurological problems or increase the obstruction.

In a comparative trial of LUPRON INJECTION (leuprolide acetate) versus DES, in 5% or more of the
patients receiving either drug, the following adverse reactions were reported to have a possible or
probable relationship to drug as ascribed by the treating physician. Often, causality is difficult to
assess in patients with metastatic prostate cancer. Reactions considered not drug related are
excluded.
LUPRON DES
(N=98) (N=101)
Number of Reports
Cardiovascular System
Congestive heart failure 1 5
ECG changes/ischemia 19 22
High blood pressure 8 5
Murmur 3 8
Peripheral edema 12 30
Phlebitis/thrombosis 2 10
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Gastrointestinal System
Anorexia 6 5
Constipation 7 9
Nausea/vomiting 5 17
Endocrine System
*Decreased testicular size 7 11
*Gynecomastia/breast tenderness or pain 7 63
*Hot flashes 55 12
*Impotence 4 12
Hemic and Lymphatic System
Anemia 5 5
Musculoskeletal System
Bone pain 5 2
Myalgia 3 9
Central/Peripheral Nervous System
Dizziness/lightheadedness 5 7
General pain 13 13
Headache 7 4
Insomnia/sleep disorders 7 5
Respiratory System
Dyspnea 2 8
Sinus congestion 5 6
Integumentary System
Dermatitis 5 8
Urogenital System
Frequency/urgency 6 8
Hematuria 6 4
Urinary tract infection 3 7
Miscellaneous
Asthenia 10 10
* Physiologic effect of decreased testosterone.

In this same study, the following adverse reactions were reported in less than 5% of the patients on
LUPRON.

Cardiovascular System—Angina, Cardiac arrhythmias, Myocardial infarction, Pulmonary emboli;

Gastrointestinal System—Diarrhea, Dysphagia, Gastrointestinal bleeding, Gastrointestinal
disturbance, Peptic ulcer, Rectal polyps; Endocrine System—Libido decrease, Thyroid enlargement;
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Musculoskeletal System—Joint pain; Central/Peripheral Nervous System—Anxiety, Blurred vision,
Lethargy, Memory disorder, Mood swings, Nervousness, Numbness, Paresthesia, Peripheral
neuropathy, Syncope/blackouts, Taste disorders; Respiratory System—Cough, Pleural rub,
Pneumonia, Pulmonary fibrosis; Integumentary System—Carcinoma of skin/ear, Dry skin,
Ecchymosis, Hair loss, Itching, Local skin reactions, Pigmentation, Skin lesions; Urogenital System—
Bladder spasms, Dysuria, Incontinence, Testicular pain, Urinary obstruction; Miscellaneous—
Depression, Diabetes, Fatigue, Fever/chills, Hypoglycemia, Increased BUN, Increased calcium,
Increased creatinine, Infection/inflammation, Ophthalmologic disorders, Swelling (temporal bone).

In an additional clinical trial and from long-term observation of both studies, the following additional
adverse events (excluding those considered not drug related) were reported for patients receiving
LUPRON.

Cardiovascular System—Bradycardia, Carotid bruit, Extrasystole, Palpitations, Perivascular cuffing

(eyes), Ruptured aortic aneurysm, Stroke, Tachycardia, Transient ischemic attack; Gastrointestinal
System—Flatus, Dryness of mouth and throat, Hepatitis, Hepatomegaly, Occult blood (rectal exam),
Rectal fistula/erythema; Endocrine System—Libido increase, Thyroid nodule; Musculoskeletal
System—Ankylosing spondylosis, Arthritis, Blurred disc margins, Bone fracture, Muscle stiffness,
Muscle tenderness, Pelvic fibrosis, Spasms/cramps; Central/Peripheral Nervous System—Auditory
hallucinations/tinnitus, Decreased hearing, Decreased reflexes, Euphoria, Hyperreflexia, Loss of
smell, Motor deficiency; Respiratory System—Chest tightness, Decreased breathing sounds,
Hemoptysis, Pleuritic chest pain, Pulmonary infiltrate, Rales/rhonchi, Rhinitis, Strep throat,
Wheezing/bronchitis; Integumentary System—Boil (pubic), Bruises, Hives, Keratosis, Mole, Shingles,
Spiders; Urogenital System— Blisters on penis, Inguinal hernia, Penile swelling, Post void residual,
Prostatic pain, Pyuria; Miscellaneous—Abdominal distention, Facial swelling/edema, Feet burning,
Flu, Eyelid growth, Hypoproteinemia, Accidental injury, Knee effusion, Mass, Pallid, Sallow,
Weakness.

Postmarketing

During postmarketing surveillance which includes other dosage forms and other patient populations,
the following adverse events were reported.

Symptoms consistent with an anaphylactoid or asthmatic process have been rarely (incidence rate of
about 0.002%) reported. Rash, urticaria, and photosensitivity reactions have also been reported.

Localized reactions including induration and abscess have been reported at the site of injection.

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Symptoms consistent with fibromyalgia (e.g., joint and muscle pain, headaches, sleep disorders,
gastrointestinal distress, and shortness of breath) have been reported individually and collectively.

Cardiovascular System – Hypotension, Myocardial infarction; Endocrine System - Diabetes;

Gastrointestinal System – Hepatic dysfunction; Hemic and Lymphatic System – Decreased WBC;
Integumentary System – Hair growth; Central/Peripheral Nervous System – Convulsion, Spinal
fracture/paralysis, Hearing disorder; Miscellaneous – Hard nodule in throat, Weight gain, Increased
uric acid; Musculoskeletal System – Tenosynovitis-like symptoms; Respiratory System – Respiratory
disorders.

Changes in Bone Density: Decreased bone density has been reported in the medical literature in men
who have had orchiectomy or who have been treated with an LH-RH agonist analog. In a clinical trial,
25 men with prostate cancer, 12 of whom had been treated previously with leuprolide acetate for at
least six months, underwent bone density studies as a result of pain. The leuprolide-treated group
had lower bone density scores than the nontreated control group. It can be anticipated that long
periods of medical castration in men will have effects on bone density.

Pituitary apoplexy: During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical
syndrome secondary to infarction of the pituitary gland) have been reported after the administration of
gonadotropin-releasing hormone agonists. In a majority of these cases, a pituitary adenoma was
diagnosed, with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and
some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache,
vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular
collapse. Immediate medical attention has been required.

See other LUPRON DEPOT and LUPRON INJECTION package inserts for other events reported in
the same and different 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 dyspnea, 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 with leuprolide acetate 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

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The recommended dose is 1 mg (0.2 mL or 20 unit mark) administered as a single daily
subcutaneous injection. As with other drugs administered chronically by subcutaneous injection, the
injection site should be varied periodically. Each 0.2 mL contains 1 mg of leuprolide acetate, sodium
chloride for tonicity adjustment, 1.8 mg of benzyl alcohol as preservative and water for injection. The
pH may have been adjusted with sodium hydroxide and/or acetic acid.

Follow the pictorial directions on the reverse side of this package insert for administration.

NOTE: As with all parenteral products, inspect the solution for discoloration and particulate matter
before each use.

HOW SUPPLIED

LUPRON INJECTION (leuprolide acetate) is a sterile solution supplied in a 2.8 mL multiple-dose vial.
The vial is packaged as follows: 14 Day Patient Administration Kit with 14 disposable syringes and 28
alcohol swabs, NDC 0074-3612-30 and six-vial carton, NDC 0074-3612-34.

Store below 77°F (25°C). Do not freeze. Protect from light; store vial in carton until use.

U.S. Patent Nos. 4,005,063 and 4,005,194.

REFERENCES
1. Taylor, JD. Anaphylactic reaction to LHRH analogue, leuprorelin. Med J Australia 1994 Oct;
161(3): 455.
2. Letterie GS, et al. Recurrent anaphylaxis to a depot form of GnRH analogue. Obstet Gynecol
1991 Nov; 78: 943–946.

INFORMATION FOR PATIENTS

Be sure to consult your physician with any questions you may have or for information about LUPRON
INJECTION (leuprolide acetate) and its use.

WHAT IS LUPRON?

LUPRON INJECTION (leuprolide acetate) is chemically similar to gonadotropin releasing hormone

(GnRH or LH-RH) a hormone which occurs naturally in your body.

Normally, your body releases small amounts of LH-RH and this leads to events which stimulate the
production of sex hormones.

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However, when you inject LUPRON INJECTION (leuprolide acetate), the normal events that lead to
sex hormone production are interrupted and testosterone is no longer produced by the testes.

LUPRON must be injected because, like insulin which is injected by diabetics, LUPRON is inactive
when taken by mouth.

If you were to discontinue the drug for any reason, your body would begin making testosterone again.

DIRECTIONS FOR USING LUPRON

1. Wash hands thoroughly with soap and water.
2. If using a new bottle for the first time, flip off the plastic cover to expose the grey rubber
stopper. Wipe metal ring and rubber stopper with an alcohol wipe each time you use LUPRON.
Check the liquid in the container. If it is not clear or has particles in it, DO NOT USE IT.
Exchange it at your pharmacy for another container.
3. Remove outer wrapping from one syringe. Pull plunger back until the tip of the plunger is at the
0.2 mL or 20 unit mark.
4. Take cover off needle. Push the needle through the center of the rubber stopper on the
LUPRON bottle.
5. Push the plunger all the way in to inject air into the bottle.
6. Keep the needle in the bottle and turn the bottle upside down. Check to make sure the tip of
the needle is in the liquid. Slowly pull back on the plunger, until the syringe fills to the 0.2 mL or
20 unit mark.
7. Toward the end of a two-week period, the amount of LUPRON left in the bottle will be small.
Take special care to hold the bottle straight and to keep the needle tip in liquid while pulling
back on the plunger.
8. Keeping the needle in the bottle and the bottle upside down, check for air bubbles in the
syringe. If you see any, push the plunger slowly in to push the air bubble back into the bottle.
Keep the tip of the needle in the liquid and pull the plunger back again to fill to the 0.2 mL or 20
unit mark.
9. Do this again if necessary to eliminate air bubbles.
10. To protect your skin, inject each daily dose at a different body spot.
11. Choose an injection spot. Cleanse the injection spot with another alcohol wipe.
12. Hold the syringe in one hand. Hold the skin taut, or pull up a little flesh with the other hand, as
you were instructed.

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 13. Holding the syringe as you would a pencil, thrust the needle all the way into the skin at a 90°
angle. Push the plunger to administer the injection.
14. Hold an alcohol wipe down on your skin where the needle is inserted and withdraw the needle
at the same angle it was inserted.
15. Use the disposable syringe only once and dispose of it properly as you were instructed.
Needles thrown into a garbage bag could accidentally stick someone. NEVER LEAVE
SYRINGES, NEEDLES OR DRUGS WHERE CHILDREN CAN REACH THEM.

SOME SPECIAL ADVICE

• You may experience hot flashes when using LUPRON INJECTION (leuprolide acetate). During
the first few weeks of treatment you may experience increased bone pain, increased difficulty
in urinating, and less commonly but most importantly, you may experience the onset or
aggravation of nerve symptoms. In any of these events, discuss the symptoms with your
doctor. Like other treatment options, LUPRON may cause impotence. Notify your doctor if you
develop new or worsened symptoms after beginning LUPRON treatment.
• You may experience some irritation at the injection site, such as burning, itching or swelling.
These reactions are usually mild and go away. If they do not, tell your doctor.
• If you have experienced an allergic reaction to other drugs like LUPRON, you should not use
this drug.
• Do not stop taking your injections because you feel better. You need an injection every day to
make sure LUPRON keeps working for you.
• If you need to use an alternate to the syringe supplied with LUPRON, low-dose insulin syringes
should be utilized.
• When the drug level gets low, take special care to hold the bottle straight up and down and to
keep the needle tip in liquid while pulling back on the plunger.
• Do not try to get every last drop out of the bottle. This will increase the possibility of drawing air
into the syringe and getting an incomplete dose. Some extra drug has been provided so that
you can withdraw the recommended number of doses.
• Tell your pharmacist when you will need LUPRON so it will be at the pharmacy when you need
it.
• Store below 77°F (25°C). Do not store near a radiator or other very warm place. Do not freeze.
Protect from light; store vial in carton until use.
• Do not leave your drug or hypodermic syringes where anyone can pick them up.
• Keep this and all other medications out of reach of children.
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Manufactured for
Abbott Laboratories
North Chicago, IL 60064, U.S.A.

® – Registered
(No. 3612)
December, 2008
© 2008 Abbott Laboratories

For Pediatric Use

LUPRON® INJECTION
(leuprolide acetate)

Rx only

DESCRIPTION

Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin releasing

hormone (GnRH or LH-RH). The analog possesses greater potency than the natural hormone. The
chemical name is 5- oxo -L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-
N-ethyl-L-prolinamide acetate (salt) with the following structural formula:

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

It is available in a 2.8 mL multiple dose vial containing leuprolide acetate (5 mg/mL), sodium chloride,
USP (6.3 mg/mL) for tonicity adjustment, benzyl alcohol, NF as a preservative (9 mg/mL), and water
for injection, USP. The pH may have been adjusted with sodium hydroxide, NF and/or acetic acid,
NF.

CLINICAL PHARMACOLOGY

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

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Leuprolide acetate is not active when given orally.

Pharmacokinetics

A pharmacokinetic study of leuprolide acetate in children has not been performed.

Absorption

In adults, bioavailability by subcutaneous administration is comparable to that by intravenous

administration.

Distribution

The mean steady-state volume of distribution of leuprolide following intravenous bolus administration
to healthy adult male volunteers was 27 L. In vitro binding to human plasma proteins ranged from
43% to 49%.

Metabolism

In healthy adult male volunteers, a 1 mg bolus of leuprolide administered intravenously revealed that
the mean systemic clearance was 7.6 L/h, with a terminal elimination half-life of approximately 3
hours based on a two compartment model.

In rats and dogs, administration of 14C-labeled leuprolide was shown to be metabolized to smaller
inactive peptides, a pentapeptide (Metabolite I), tripeptides (Metabolites II and III) and a dipeptide
(Metabolite IV). These fragments may be further catabolized.

The major metabolite (M-I) plasma concentrations measured in 5 prostate cancer patients reached
maximum concentration 2 to 6 hours after dosing and were approximately 6% of the peak parent drug
concentration. One week after dosing, mean plasma M-I concentrations were approximately 20% of
mean leuprolide concentrations.

Excretion

Following administration of LUPRON DEPOT 3.75 mg to three adult patients, less than 5% of the
dose was recovered as parent and M-I metabolite in the urine.

Special Populations

The pharmacokinetics of the drug in hepatically and renally impaired patients has not been
determined.

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Drug Interactions

No pharmacokinetic-based drug-drug interaction studies have been conducted with leuprolide

acetate. However, because leuprolide acetate is a peptide that is primarily degraded by peptidase
and the drug is only about 46% bound to plasma proteins, drug interactions would not be expected to
occur.

CLINICAL STUDIES

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 psychological growth and
development. 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. Organ Growth. Reproductive organs will return to a prepubertal state.
3. Menses. Menses, if present, will cease.

INDICATIONS AND USAGE

LUPRON INJECTION is 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 confirmed prior to initiation of therapy:
• Confirmation of diagnosis by a pubertal response to a GnRH stimulation test. The
sensitivity and methodology of this assay must be understood.
• Bone age advanced 1 year beyond the chronological age.
3. Baseline evaluation should also include:
• Height and weight measurements.
• Sex steroid levels.
• Adrenal steroid level to exclude congenital adrenal hyperplasia.

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 • Beta human chorionic gonadotropin level to rule out a chorionic gonadotropin secreting
tumor.
• Pelvic/adrenal/testicular ultrasound to rule out a steroid secreting tumor.
• Computerized tomography of the head to rule out intracranial tumor.

CONTRAINDICATIONS
1. Hypersensitivity to GnRH, GnRH agonist analogs or any of the excipients in LUPRON
INJECTION. Reports of anaphylactic reactions to GnRH agonist analogs have been reported
in the medical literature.1,2
2. LUPRON is contraindicated in women who are or may become pregnant while receiving the
drug. LUPRON may cause fetal harm when administered to a pregnant woman. Major fetal
abnormalities were observed in rabbits but not in rats after administration of leuprolide acetate
throughout gestation. There was increased fetal mortality and decreased fetal weights in rats
and rabbits. (See PRECAUTIONS, Pregnancy, Teratogenic Effects section.) The effects on
fetal mortality are expected 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. If this drug is administered during pregnancy or if the patient
becomes pregnant while taking any formulation of LUPRON, the patient should be apprised of
the potential hazard to the fetus.

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 symptoms 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
menses, breast development, and testicular growth. The long-term consequences of inadequate
control of gonadal steroid secretion 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 symptoms of hypersensitivity, usually local, in the form of erythema and induration at the
injection site.
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Information for Parents

Prior to starting therapy with LUPRON INJECTION, the parent or guardian must be aware of the
importance of continuous therapy. Adherence to daily drug administration schedules must be
accepted if therapy is to be successful. Irregular dosing could restart the maturation process.
• During the first 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. If the child
has experienced an allergic reaction to other drugs like LUPRON, this drug should not be
used.
• Report any unusual signs or symptoms to the physician, like continued pubertal changes,
substantial mood swings or behavioral changes.

Laboratory Tests

Response to leuprolide acetate should be monitored 1-2 months after the start of therapy with a
GnRH stimulation test and sex steroid levels. Measurement 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
WARNINGS section). Once a therapeutic dose has been established, gonadotropin and sex steroid
levels will decline to prepubertal levels.

Drug Interactions

See CLINICAL PHARMACOLOGY, Pharmacokinetics section.

Drug/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.

Carcinogenesis, Mutagenesis, 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 of 0.6 to 4 mg/kg (>100 times the clinical doses
of 7.5 to 15 mg/month based on body surface area). There was a significant but not dose-related
Reference ID: 2920484
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 daily dose as high as 60 mg/kg (>5000 times the clinical doses based
on body surface area). Adult patients have been treated with leuprolide acetate for up to three years
with doses as high as 10 mg/day and for two years with doses as high as 20 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 GnRH 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 offspring of the treated animals appeared normal. The effect of the treatment of the
parents on the reproductive performance of the F1 generation was not tested. The clinical
significance of these findings is unknown.

Pregnancy

Teratogenic Effects

Pregnancy Category X

(see CONTRAINDICATIONS section)

When administered on day 6 of pregnancy at test dosages of 0.00024, 0.0024, and 0.024 mg/kg
(1/1200 to 1/12 the human pediatric dose) to rabbits, LUPRON 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 in rabbits and with the highest dose in rats.

Nursing Mothers

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

Geriatric Use

Reference ID: 2920484

See labeling for LUPRON INJECTION for the pharmacokinetics, efficacy and safety of LUPRON in
this population.

ADVERSE REACTIONS

Clinical Trials:

Potential exacerbation of signs and symptoms during the first few weeks of treatment (see
PRECAUTIONS 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
N = 421 (Percent)
Body as a Whole
General Pain 12 (3)
Headache 11 (3)
Injection Site Reactions Including Abscess* 37 (9)
Cardiovascular System
Vasodilation 9 (2)
Integumentary System (Skin and Appendages)
Acne/Seborrhea 13 (3)
Rash Including Erythema Multiforme 12 (3)
Nervous System
Emotional Lability 19 (5)
Urogenital System
Vaginitis/Vaginal Bleeding/Vaginal Discharge 13 (3)

* Most events were mild or moderate in severity.

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

Body as a Whole – Aggravation of preexisting tumor and decreased vision, Allergic Reaction, Body
Odor, Fever, Flu Syndrome, Hypertrophy, Infection; Cardiovascular System – Bradycardia,
Hypertension, Peripheral Vascular Disorder, Syncope; Digestive System – Constipation, Dyspepsia,
Dysphagia, Gingivitis, Increased Appetite, Nausea/Vomiting; Endocrine System - Accelerated Sexual
Maturity, Feminization, Goiter; Hemic and Lymphatic System – Purpura; Metabolic and Nutritional
Disorders – Growth Retarded, Peripheral Edema, Weight Gain; Musculoskeletal System – Arthralgia,
Joint Disorder, Myalgia, Myopathy; Nervous System – Depression, Hyperkinesia, Nervousness,
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Somnolence; Respiratory System – Asthma, Epistaxis, Pharyngitis, Rhinitis, Sinusitis; Integumentary
System (Skin and Appendages) - Alopecia, Hair Disorder, Hirutism, Leukoderma, Nail Disorder, Skin
Hypertrophy; Urogenital System - Cervix Disorder/Neoplasm, Dysmenorrhea, Gynecomastia/Breast
Disorders, Menstrual Disorder, Urinary Incontinence.

Laboratory: The following laboratory events were reported as adverse reactions, antinuclear antibody
present and increased sedimentation rate.

Postmarketing

During postmarketing surveillance, which includes other dosage forms and other patient populations,
the following adverse events were reported.

Symptoms consistent with an anaphylactoid or asthmatic process have been rarely (incidence rate of
about 0.002%) reported. Rash, urticaria, and photosensitivity reactions have also been reported.
Localized reactions including induration and abscess have been reported at the site of injection.
Symptoms consistent with fibromyalgia (e.g., joint and muscle pain, headaches, sleep disorders,
gastrointestinal distress, and shortness of breath) have been reported individually and collectively.

Cardiovascular System – Hypotension, Pulmonary embolism; Gastrointestinal System – Hepatic

dysfunction; Hemic and Lymphatic System – Decreased WBC; Integumentary System – Hair growth;
Central/Peripheral Nervous System – Peripheral neuropathy, Convulsion, Spinal fracture/paralysis,
Hearing disorder; Miscellaneous – Hard nodule in throat, Weight gain, Increased uric acid;
Musculoskeletal System –Tenosynovitis-like symptoms; Respiratory System – Respiratory disorders;
Urogenital System – Prostate pain.

Changes in Bone Density: Decreased bone density has been reported in the medical literature in men
who have had orchiectomy or who have been treated with an LH-RH agonist analog. In a clinical trial,
25 men with prostate cancer, 12 of whom had been treated previously with leuprolide acetate for at
least six months, underwent bone density studies as a result of pain. The leuprolide-treated group
had lower bone density scores than the nontreated control group. The effects on bone density in
children are unknown.

Pituitary apoplexy: During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical
syndrome secondary to infarction of the pituitary gland) have been reported after the administration of
gonadotropin-releasing hormone agonists. In a majority of these cases, a pituitary adenoma was
diagnosed, with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and
some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache,
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vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular
collapse. Immediate medical attention has been required.

See other LUPRON INJECTION and LUPRON DEPOT package inserts for adverse events reported
in other patient populations.

OVERDOSAGE

In rats, subcutaneous administration of 125 to 250 times the recommended human pediatric dose,
expressed on a per body weight basis, resulted in dyspnea, 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 INJECTION can be administered by a patient/parent or health care professional.

The dose of LUPRON INJECTION must be individualized for each child. The dose is based on a
mg/kg ratio of drug to body weight. Younger children require higher doses on a mg/kg ratio.

After 1-2 months of initiating therapy or changing doses, the child must be monitored with a GnRH
stimulation test, sex steroids, and Tanner staging to confirm 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.

The first dose found to result in adequate downregulation can probably be maintained for the duration
of therapy in most children. However, there are insufficient data to guide dosage adjustment as
patients move into higher weight categories after beginning therapy at very young ages and low
dosages. It is recommended that adequate downregulation be verified in such patients whose weight
has increased significantly while on therapy.

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

Discontinuation of LUPRON INJECTION should be considered before age 11 for females and age 12
for males.

The recommended starting dose is 50 mcg/kg/day administered as a single subcutaneous injection. If

total downregulation is not achieved, the dose should be titrated upward by 10 mcg/kg/day. This dose
will be considered the maintenance dose.
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Follow the pictorial directions on the reverse side of this package insert for administration.

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

HOW SUPPLIED

LUPRON INJECTION (leuprolide acetate) is a sterile solution supplied in a 2.8 mL multiple-dose vial.
The vial is packaged as follows:
• 14 Day Patient Administration Kit with 14 disposable syringes and 28 alcohol swabs, NDC
0074-3612-30.
• Six-vial carton, NDC 0074-3612-34.
• Store below 77°F (25°C). Do not freeze. Protect from light; store vial in carton until use.
• Use the syringes supplied with LUPRON INJECTION. Insulin syringes may be substituted for
use with LUPRON INJECTION.

U.S. Patent Nos. 4,005,063; 4,005,194.

REFERENCES
1. Taylor, JD. Anaphylactic reaction to LHRH analogue, leuprorelin. Med J Australia 1994 Oct;
161(3): 455.
2. Letterie GS, et al. Recurrent anaphylaxis to a depot form of GnRH analogue. Obstet Gynecol
1991 Nov; 78: 943–946.

Manufactured for
Abbott Laboratories
North Chicago, IL 60064, U.S.A.

® – Registered

(No. 3612)

ADMINISTERING THE INJECTION

Read this booklet before injecting the medication. Read the complete instructions for injection.

Abbott Laboratories
North Chicago, IL 60064, U.S.A.
Reference ID: 2920484
(No. 3612)
December, 2008

© 2008 Abbott Laboratories

Provided as an educational service by

Abbott Laboratories

Abbott Laboratories
North Chicago, IL 60064, U.S.A.

ADMINISTERING THE INJECTION

1.
Wash hands thoroughly.

2.
Check the liquid in the container. It should look clear. DO NOT USE if it is not clear or if it has
particles in it. If using a new bottle, flip off the plastic cover to expose the grey rubber stopper.
Use an alcohol swab to cleanse the metal ring and rubber stopper on medication bottle every
day, just before you use it.

3.
Remove outer wrapping from one syringe.

4.
Pull the syringe plunger back until its tip is at the proper mark.

5.
Uncover needle. Do not touch the needle.

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 6.
Place the bottle on a clean, flat surface and push the needle through the center of the rubber
stopper on the bottle. Push the plunger all the way in to inject air into the bottle.

7.
Keep the needle in the bottle.
Lift the bottle and turn it straight upside down.
Check to see that the needle tip is in the liquid.

8.
With the needle tip in the liquid, slowly pull back the plunger until syringe fills to the proper
mark.
If any bubbles appear in the syringe, remove them by pushing the plunger up slowly.
With the needle tip still in the liquid, pull the plunger until it is once more at the proper mark.

9.
Choose a different injection site each day.
Cleanse the injection site with a new alcohol swab.
Hold the skin the way you were instructed.
Slide the needle quickly all the way through the skin, into the subcutaneous tissue, at a 90°
angle.

10.
Push the plunger to inject the medication.
Withdraw the needle at the same angle it was inserted (90°).
Wipe the skin with an alcohol swab.

11.
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 Dispose of the syringe and alcohol swabs as you were instructed.
Remember: use the disposable syringe only once.

Abbott Laboratories

Reference ID: 2920484