Download Lucrin® PDs Depot 3.75 mg

Prescribing Information
changes occur within a month of initiating drug therapy at recommended
doses.
NAME OF THE MEDICINAL
PRODUCT
Prescribing
Information
Lucrin PDS Depot 3.75 mg
®
NAME OF THE MEDICINAL PRODUCT
®
(Leuprorelin
Acetate
for Depot
Suspension
Lucrin
PDS
Depot
3.75
mg 3.75 mg)
(Leuprorelin Acetate for Depot Suspension 3.75 mg)
DESCRIPTION
DESCRIPTION
Leuprorelin acetate is a synthetic nonapeptide analog of naturally
Leuprorelin
acetate
is a synthetic
nonapeptide
analogue
of naturally
occurring
occurring
gonadotropin
releasing
hormone (GnRH
or LHRH).
The analogue
gonadotrophin
hormonethan
(GnRH
LHRH). hormone.
The analogue possesses greater
possesses releasing
greater potency
theornatural
potency than the natural hormone.
The chemical name is 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-LThe chemical name is 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucylL-leucyl-L-arginyl-N-ethyl-L-prolinamide acetate (salt) and the structural formula is
as follows:
NH2
N
H N
O
N
H
N
O
CH2 H
N
O
O
CH2 H
OH
CH3
H3C CH
CH2 H
O
N
N
H
O
CH2 H
N
CH2 H
O
N
Serum levels of leuprorelin acetate 3.75 mg measured in 11 patients
H
CH2
N
N
CH2 H
O
H3C CH
O
N
1-2 CH3CO
O
CH3
N
H
C NH
NH
CH2
CH2
Pharmacokinetics
For
patients at risk, the physician may consider initiating therapy with daily leuprorelin
acetate
injection
for the
weeks
to given
facilitate
withdrawal
of treatment
Leuprorelin
acetate
is first
not two
active
when
orally.
Bioavailability
of thisif that
isagent
considered
necessary.
following
subcutaneous administration is comparable to that after
Patients
with metastatic
vertebral lesions and/or urinary tract obstruction should be
intramuscular
administration.
closely observed during the first few weeks of therapy.
Absorption
Hyperglycemia and an increased risk of developing diabetes have been reported in
Following
single
administration
of Leuprorelin
Acetate
for Depot
men
receivingaGnRH
agonists.
Hyperglycemia
may represent
development
of diabetes
Suspension
in prostatic
carcinoma
patients,
doses
of diabetes.
3.75 mg Monitor
and 7.5blood
mellitus
or worsening
of glycemic
control
in patients
with
mg by and/or
subcutaneous
and intramuscular
routes provided
mean
leuprorelin
glucose
glycosylated
hemoglobin (HbA1c)
periodically
in patients
receiving
GnRH
agonists,
and
manage with current
practice
for treatment
acetate
plasma
concentrations
at the end
of one
month of of
0.7hyperglycemia
ng/mL
orand
diabetes.
1.0 ng/mL, respectively. There was no indication of any drug
accumulation.
Intramuscular
injectioninfarction,
of the depot
formulation
(7.5and
mg)stroke
Increased
risk of developing
myocardial
sudden
cardiac death
has
been
reported
in association
use of GnRHof
agonists
in men.
The risk
appears
was
shown
to provide
plasmawith
concentrations
leuprorelin
acetate
over
low
based on
reported
be evaluated
carefully
along with
a period
ofthe
one
monthodds
in aratios,
studyand
of should
orchiectomized
male
patients.
cardiovascular
risk factors
whenacetate
determining
a treatment
for patients
with
prostate
Similarly, mean
leuprorelin
levels
were detectable
after
four
cancer. Patients receiving GnRH agonists should be monitored for symptoms and signs
weeks of a single 7.5 mg, I.M., Leuprorelin Acetate for Depot Suspension
suggestive of development of cardiovascular disease and be managed according to
in a study
involving
current
clinical
practice.stage D2 prostatic carcinoma patients.
OH
Leuprorelin
Acetate
for Depot
Suspension
is a formulation
of leuprorelin
Leuprorelin
Acetate
for Depot
Suspension
is a formulation
of leuprorelin
acetate
acetate
supplied
as sterile
lyophilizedWhen
microspheres.
with a
supplied
as sterile
lyophilized
microspheres.
mixed withWhen
diluent,mixed
it becomes
diluent,
it
becomes
a
suspension
which
is
administered
as
an
intramuscular
suspension for injection, which is administered as an intramuscular or subcutaneous
injection
once a month.
or subcutaneous
injection once a month.
Active/Inactive
Ingredients
Active/Inactive
Ingredients
Leuprorelin Acetate for Depot Suspension 3.75 mg contains the following
Leuprorelin
Acetate
for Depot Suspension 3.75 mg
ingredients:
Leuprorelin
Acetate
for Depot
3.75 mg
contains
following
Leuprorelin
acetate
(3.75 mg),
gelatinSuspension
(0.65 mg), DL-lactic
and
glycolicthe
acids
copolymer
leuprorelin
acetate (3.75 mg), purified gelatin (0.65 mg),
(33.1ingredients:
mg), and mannitol
(6.6 mg).
DL-lactic
and
glycolic
acids
copolymer
(33.1
mg),
and
D-mannitol
During the manufacture of Leuprorelin Acetate for Depot Suspension 3.75 mg, acetic
(6.6
mg).
acid is
lost,
leaving the peptide.
The accompanying
diluent contains
carboxymethylcellulose
sodium
mg), mannitol
During the manufacture
of Leuprorelin
Acetate for
Depot(5Suspension
(50 mg),
(1 mg),
water
for injection
(1 mL).
3.75polysorbate
mg, acetic80
acid
is lost,
leaving
the peptide.
The accompanying diluent contains carboxymethylcellulose sodium
CLINICAL
(5 mg),PHARMACOLOGY
D-mannitol (50 mg), polysorbate 80 (1 mg), water for injection
(1 mL), and glacial acetic acid, to control pH.
Pharmacodynamics
Leuprorelin acetate, a GnRH agonist, acts as a potent inhibitor of gonadotrophin
CLINICAL
PHARMACOLOGY
secretion
when given
on a continuous basis and in therapeutic doses. Animal and
human
studies indicate that following an initial stimulation, chronic administration
Pharmacodynamics
of leuprorelin acetate results in suppression of ovarian and testicular steroidogenesis.
Leuprorelin
acetate,
a GnRH agonist,
acts as a potent inhibitor of
This effect
is reversible
on discontinuation
of therapy.
gonadotropin
secretionacetate
when has
given
on aincontinuous
and inof
Administration
of leuprorelin
resulted
inhibition ofbasis
the growth
therapeutic
Animal
and (prostatic
human studies
an
certain
hormone doses.
dependent
tumors
tumorsindicate
in Nobelthat
andfollowing
Dunning male
initial
stimulation, mammary
chronic administration
of rats),
leuprorelin
results
rats and
DMBA-induced
tumors in female
as wellacetate
as atrophy
of the
reproductive
organs. of ovarian and testicular steroidogenesis. This effect is
in suppression
reversible
on discontinuation
ofacetate
therapy.
In humans,
administration
of leuprorelin
results in an initial increase in circulating
levelsAdministration
of luteinizing hormone
(LH) and acetate
follicle stimulating
hormone
(FSH), leading
to a
of leuprorelin
has resulted
in inhibition
of the
transient increase in levels of the gonadal steroids (testosterone and dihydrotestosterone
growth of certain hormone dependent tumors (prostatic tumors in Nobel
in males, and estrone and estradiol in pre-menopausal females).
and Dunning male rats and DMBA-induced mammary tumors in female
However,
administration
of leuprorelinorgans.
acetate results in decreased
rats), continuous
as well as atrophy
of the reproductive
levels of LH and FSH and sex steroids. In males, testosterone is reduced to castrate
In humans,
administration
of leuprorelin
in an initial
or prepubertal
levels.
In pre-menopausal
females, acetate
estrogensresults
are reduced
to postmenopausal
These hormonal
occur within
a month
of and
initiating
drug
increaselevels.
in circulating
levelschanges
of luteinizing
hormone
(LH)
follicle
therapy
at recommended
doses.
stimulating
hormone
(FSH), leading to a transient increase in levels of
the gonadal steroids (testosterone and dihydrotestosterone in males,
Pharmacokinetics
and estrone and estradiol in pre-menopausal females).
Leuprorelin acetate is not active when given orally. Bioavailability of this agent
However,
continuous
administration
of leuprorelin
results in
following
subcutaneous
administration
is comparable
to thatacetate
after intramuscular
decreased levels of LH and FSH and sex steroids. In males, testosterone
administration.
is reduced to castrate or prepubertal levels. In pre-menopausal females,
Absorption
estrogens are reduced to post-menopausal levels. These hormonal
Following a single administration of Leuprorelin Acetate for Depot Suspension in
prostatic carcinoma patients, doses of 3.75 mg and 7.5 mg by subcutaneous and
intramuscular routes provided mean leuprorelin acetate plasma concentrations at the
end of one month of 0.7 ng/mL and 1.0 ng/mL, respectively. There was no indication
of any drug accumulation. Intramuscular injection of the depot formulation (7.5 mg)
was shown to provide plasma concentrations of leuprorelin acetate over a period of
one month in a study of orchiectomized male patients.
Similarly, mean leuprorelin acetate levels were detectable after four weeks of a single
7.5 mg, I.M., Leuprorelin Acetate for Depot Suspension in a study involving stage D2
prostatic carcinoma patients.
Serum levels of leuprorelin acetate 3.75 mg measured in 11 patients with pre-menopausal
breast cancer over 12 weeks. Mean leuprorelin acetate levels were above 0.1 ng/mL
after four weeks and remained stable after re-injection (at 8 and 12 weeks). There
was no tendency for drug accumulation.
Distribution
The mean steady-state volume of distribution of leuprorelin 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 leuprorelin administered intravenously,
revealed that the mean systemic clearance was 7.6 L/h, with a terminal elimination
half-life of approximately three hours based on a two compartment model.
Animal studies have shown 14C-labeled leuprorelin was metabolized into smaller
inactive peptides, a pentapeptide (Metabolite I), tripeptides (Metabolites II and III) and
a dipeptide (Metabolite IV). These fragments may be further metabolized.
The major metabolite (M-I) plasma concentrations measured in five prostate cancer
patients given leuprorelin acetate depot suspension reached a maximum concentration
two to six 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 leuprorelin concentrations.
Excretion
Following administration of Leuprorelin Acetate for Depot Suspension 3.75 mg to
three patients, less than 5% of the dose was recovered as parent and M-I metabolite
in the urine over 27 days.
Special Populations
The pharmacokinetics of the drug in hepatic- and renal-impaired patients has not
been determined.
INDICATIONS
Prostate Cancer
Leuprorelin Acetate for Depot Suspension 3.75 mg is indicated in the palliative
treatment of advanced prostatic cancer.
It offers an alternative treatment of prostatic cancer when orchiectomy or estrogen
administration are either not indicated or unacceptable to the patient.
Endometriosis
Leuprorelin Acetate for Depot Suspension 3.75 mg is indicated in the treatment of
endometriosis for a period of six months. It can be used as sole therapy or as an
adjunct to surgery.
Uterine Fibroids
Leuprorelin Acetate for Depot Suspension 3.75 mg is also indicated in the treatment
of leiomyoma uteri (uterine fibroids) for a period up to six months. Therapy may be
preoperative prior to myomectomy or hysterectomy, or it may provide symptomatic
relief for the perimenopausal woman who does not desire surgery.
Breast Cancer
Leuprorelin Acetate for Depot Suspension 1 month 3.75 mg is indicated for the
treatment of breast cancer in pre- and peri-menopausal women in whom hormone
therapy is specified.
CONTRAINDICATIONS
Leuprorelin Acetate for Depot Suspension is contraindicated in patients with
known hypersensitivity to leuprorelin acetate, similar nonapeptides, or any of the
excipients.
Isolated cases of anaphylaxis have been reported with the monthly formulation of
Leuprorelin Acetate for Depot Suspension.
Undiagnosed abnormal vaginal bleeding.
Leuprorelin Acetate for Depot Suspension is contraindicated in women who are, or
may become pregnant while receiving the drug.
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 leuprorelin acetate 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 fetal abnormalities and spontaneous
abortion may occur if the drug is administered during pregnancy.
Use in women who are breastfeeding (see Lactation section).
WARNINGS and PRECAUTIONS
All Populations
During the early phase of therapy, gonadotrophins 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.
Worsening of pre-existing signs and symptoms during the first weeks of treatment
may occur.
Worsening of symptoms may contribute to paralysis with or without fatal
complications.
Bone Mineral Density
Bone mineral density changes can occur during any hypoestrogenic state in women and
in long-term use in prostate cancer in men. There is no data in men regarding reversibility
after withdrawal of leuprorelin acetate. In women, bone mineral density loss may be
reversible after withdrawal of leuprorelin acetate (see ADVERSE REACTIONS).
Convulsions
Postmarketing reports of convulsions have been observed in patients on leuprorelin
acetate therapy. These included patients in the female and pediatric populations, patients
with a history of seizures, epilepsy, cerebrovascular disorders, central nervous system
anomalies or tumors, and in patients on concomitant medications that have been
associated with convulsions such as bupropion and SSRIs. Convulsions have also been
reported in patients in the absence of any of the conditions mentioned above.
Effect on QT/QTc Interval
with pre-menopausal breast cancer over 12 weeks. Mean leuprorelin
QT-prolongation
been
observed
during long-term
deprivation
therapy.
acetate levels has
were
above
0.1 ng/mL
after fourandrogen
weeks and
remained
Physicians should consider whether the benefits of androgen deprivation therapy
stable after
re-injection
8 and 12with
weeks).
Therelong
wasQT
nosyndrome,
tendencyelectrolyte
for
outweigh
the potential
risks(at
in patients
congenital
drug accumulation.
abnormalities,
or congestive heart failure and in patients taking Class IA (e.g., quinidine,
procainamide)
Distribution or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications.
Prostate Cancer
Post Marketing
Breast Cancer
3.75 mg
Leuprorelin
Acetate
Depot Suspension
1 month 3.75 mg isFrequency
indicated
System Organ
ClassforPreferred
Term
Frequency
for the treatment of breast cancer in pre- and peri-menopausal women
in whom
hormone
Endocrine
disorders therapy
Goiter is specified.
Not known
Pituitary apoplexy
Not known
CONTRAINDICATIONS
Metabolism and
Anorexia
Common
Leuprorelin
Acetate for Depot Suspension is contraindicated in patients
nutrition disorders
Diabetes mellitus
Not known
with known hypersensitivity
to leuprorelin acetate, similar nonapeptides,
Increased appetite
Not known
or any of the excipients.
Hyperglycaemia
Isolated cases of anaphylaxis
have beenUncommon
reported with the monthly
Hypoglycaemia
formulation of Leuprorelin
Acetate for Depot Suspension. Not known
Dehydration
Not known
Undiagnosed abnormal
vaginal bleeding.
Notwomen
known
Leuprorelin Acetate forHyperlipidaemia
Depot Suspension is contraindicated in
who may become pregnant
while receiving the drug.
Hyperphosphatemia
Not known
Use in women who areHypoproteinemia
breastfeeding (see Nursing Mothers section).
Not known
Abnormal weight
Uncommon
WARNINGS
gain
Prostate
Cancer
Psychiatric
disorders
Mood swings
Not known
Isolated cases of worsening
signs and symptoms during theNot
first
few
Nervousness
known
weeks of treatment have
been
reported with
GnRH analogs. Worsening
Libido
decreased
Common
The mean steady-state volume of distribution of leuprorelin following
of symptoms may contribute to paralysis with or without fatal
Laboratory Tests
Libido increased
Not known
intravenous bolus administration to healthy male volunteers was 27 L.
complications. For patients at risk, the physician may consider initiating
Response
to leuprorelin
acetate
shouldproteins
be monitored
measuring
serum
levels of
Insomnia
Uncommon
Not known
In vitro binding
to human
plasma
rangedbyfrom
43% to
49%.
testosterone, as well as prostate specific antigen and prostatic acid phosphatase. therapy with daily leuprorelin acetate injection for the first two weeks
disorder
Uncommon
Not known
of treatment
if that
is considered necessary.
InMetabolism
the majority of patients, testosterone levels increased above baseline during the to facilitate withdrawalSleep
In healthy
male volunteers,
a baseline
1 mg bolus
first
week, declining
thereafter to
levelsof
orleuprorelin
below by theadministered
end of the second
Depression
Uncommon
Not known
Endometriosis/Uterine
Fibroids
week
of treatment.
Castrate
were reached
two to
four
intravenously,
revealed
thatlevels
the mean
systemicwithin
clearance
was
7.6weeks
L/h, and
Anxiety
Not known
once
were
maintainedhalf-life
for as long
as the patientsthree
received
their
injections During the early phase of therapy, sex steroids temporarily rise above
withachieved
a terminal
elimination
of approximately
hours
based
Delusion
Not known
on
Transient
increases
in acid phosphatase levels sometimes occurred early baseline because of the
physiological effect of the drug. Therefore,
an
ontime.
a two
compartment
model.
in treatment. However, by the fourth
week, the elevated levels usually decrease to increase in clinical signs
andideation
symptoms may be observed during
the
Suicidal
Not known
14
Animal
studies
have shown C-labeled leuprorelin was metabolized
values
at or
near baseline.
initial days of therapy,Suicidal
but these
will dissipate with continued
attempt
Nottherapy
known
into smaller inactive peptides, a pentapeptide (Metabolite I) tripeptides
at adequate doses. However, reports of heavy vaginal bleeding requiring
Women
(Metabolites II and III) and a dipeptide (Metabolite IV). These fragments
Nervous system
Dizziness
Uncommon
Not known
medical
or surgical intervention with continued therapy have been
disorders
may be further metabolized.
Endometriosis/Uterine
Fibroids
Headache
reported in the treatment
of submucous leiomyoma uteri. Not known
The major
metabolite
(M-I) plasma
concentrations
in five
During
the early
phase of therapy,
sex steroids
temporarily risemeasured
above baseline
because
Paraesthesia
Uncommon
Not known
Safe
use
of
leuprorelin
acetate
in pregnancy
has not been established
ofprostate
the physiological
effect ofgiven
the drug.
Therefore,
an increase
clinical signs and
cancer patients
leuprorelin
acetate
depotinsuspension
known
clinically. Before startingLethargy
treatment with leuprorelin acetate, it isNot
advisable
symptoms
may
be
observed
during
the
initial
days
of
therapy,
but
these
will
dissipate
reached a maximum concentration two to six hours after dosing and
patient is pregnant.
Leuprorelin acetate is not
with
continued
therapy at
adequate
reports
of heavy vaginal
bleeding to establish whether the
Somnolence
Uncommon
were
approximately
6%
of thedoses.
peak However,
parent drug
concentration.
One
is required, a nonhormonal method
of
requiring
medical
or surgical
with continued therapy
have been reported a contraceptive. If contraception
Memory impairment
Not known
week after
dosing,
mean intervention
plasma M-I concentrations
were approximately
in the treatment of submucous leiomyoma uteri.
contraception should be used.
20% of mean leuprorelin concentrations.
Dysgeusia
Not known
Safe use of leuprorelin acetate in pregnancy has not been established clinically. Before
Excretion
Hypoaesthesia
Not known
starting
treatment with leuprorelin acetate, it is advisable to establish whether the PRECAUTIONS
Following
administration of Leuprorelin Acetate for Depot Suspension
patient
is pregnant.
Syncope
Not known
Bone Mineral Density
3.75 mg to
threeis patients,
less than If5%
of the dose
was recovered
as
Leuprorelin
acetate
not a contraceptive.
contraception
is required,
a nonhormonal
Neuropathy
Not known
Bone mineral density changes
can occur during any hypoestrogenic
state.
parent of
and
M-I metabolite
in be
theused.
urine over 27 days.
method
contraception
should
peripheral
may be reversible after withdrawal of leuprorelin
Since
bonePopulations
loss can be anticipated as part of natural menopause, it may also be expected Bone mineral density loss
Special
Cerebrovascular
Not known
toThe
occur
during a medically-induced
Bone loss has
been found acetate.
pharmacokinetics
of the drughypoestrogenic
in hepatic- andstate.
renal-impaired
patients
accident
tohas
be not
reversible
after
completion
of
a
six
month
course
of
leuprorelin
acetate.
been determined.
Prostate Cancer
Loss of consciousness
Not known
Experience with Leuprorelin Acetate for Depot Suspension in females has been limited
Patients with metastatic
vertebral
lesions and/or urinary tract obstruction
Transient
ischemic
Not known
toINDICATIONS
women 18 years of age and older, treated for 6 months.
attack during the first few weeks of therapy (see
should be closely observed
Prostate
Cancer
Laboratory Tests
WARNINGS).
Paralysis
Not known
Response
to leuprorelin
acetate
should
be monitored
oneistoindicated
two months
after the
Leuprorelin
Acetate for
Depot
Suspension
3.75 mg
in the
Neuromyopathy
Not known
Laboratory
Tests
start
of therapy
with a GnRH
stimulation
test and
sex steroid
levels.
Measurement of
palliative
treatment
of advanced
prostatic
cancer.
It offers
an alternative
Not known
bone
age forofadvancement
should
be orchiectomy
done every 6or
toestrogen
12 months.
Response to leuprorelinConvulsion
acetate should be monitored by measuring
serum
treatment
prostatic cancer
when
administration
Eye of
disorders
blurred
known
testosterone, Vision
as well
as prostate specific antigen andNot
prostatic
Sex
steroids
may
increase or
or unacceptable
rise above pre-pubertal
levels if the dose is inadequate. levels
is either
not
indicated
to the patient.
Once a therapeutic dose has been established, gonadotrophin and sex steroid levels acid phosphatase. In the
majority
increased
Eye
disorder of patients, testosterone levelsNot
known
Endometriosis
will
decline to pre-pubertal levels.
above baseline duringVisual
the first
week, declining thereafter toNotbaseline
impairment
known
levels or below by the end of the second week of treatment. Castrate
Leuprorelin
Acetate for Depot Suspension 3.75 mg is indicated in the
Drug
Interactions
Amblyopia
Uncommon
Not known
levels were reached within
two to four weeks
and once achieved
were
treatment
of
endometriosis
for
a
period
of
six
months.
It
can
be
used
No pharmacokinetic-based drug-drug interaction studies have been conducted with
Dry eye
Not known
as sole therapy
orfor
as Depot
an adjunct
to surgery.
Leuprorelin
Acetate
Suspension.
However, because leuprorelin acetate is a maintained for as long as the patients received their injections on time.
increases in acid
phosphatase levels
sometimes occurred early
Ear and labyrinth
Ear pain
Uncommon
peptide
thatFibroids
is primarily degraded by peptidase and not by cytochrome P-450 enzymes Transient
Uterine
disorders
However,Tinnitus
by the fourth week,
the elevated levels
usually
as noted in specific studies, and the drug is only about 46% bound to plasma proteins, in treatment.
Uncommon
Not known
Leuprorelin
Acetate
Suspension
3.75 mg is also indicated in
decrease to values at or near baseline.
drug
interactions
wouldfor
notDepot
be expected
to occur.
Hearing impaired
Not known
the treatment of leiomyoma uteri (uterine fibroids) for a period up to
Drug/Laboratory Test Interactions
Administration of leuprorelin acetate depot in women results in suppression of the
pituitary-gonadal system. Normal function is usually restored within three months
after leuprorelin acetate depot treatment is discontinued. Therefore, diagnostic tests
of pituitary gonadotrophic and gonadal functions conducted during treatment and
for up to three months after discontinuation of leuprorelin acetate depot may be
misleading.
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
(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 leuprorelin acetate-induced
tumors or pituitary abnormalities were observed at a dose as high as 60 mg/kg for
two years. Patients have been treated with leuprorelin 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 leuprorelin acetate using bacterial and
mammalian systems. These studies provided no evidence of a mutagenic potential.
Clinical and pharmacologic studies in adults with leuprorelin acetate and similar
analogues have shown full reversibility of fertility suppression when the drug is
discontinued after continuous administration for periods of up to 24 weeks.
Pregnancy and Lactation
Pregnancy
See CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS.
Lactation
It is not known whether leuprorelin acetate is excreted in human milk. Therefore, it
should not be used by nursing mothers.
Cardiac disorders
Vascular disorders
Women
Metabolism and nutrition disorders: weight gain, weight loss
Psychiatric disorders: loss of or decreased libido, increased libido, affects lability
Nervous system disorders: headache
Vascular disorders: hot flushes, vasodilatation, hypotension
Skin and subcutaneous tissue disorders: acne, seborrhea, dry skin, urticaria,
skin odour abnormal, hyperhidrosis, hair growth abnormal, hirsutism, hair disorder,
eczema, nail disorder, night sweats
Reproductive system and breast disorders: vaginal haemorrhage, dysmenorrhea,
menstrual disorder, breast enlargement, breast engorgement, breast atrophy, genital
discharge, vaginal discharge, galactorrhea, breast pain, metrorrhagia, menopausal
symptoms, dyspareunia, uterine disorder, vaginitis, menorrhagia
General disorders and administration site conditions: feeling hot, irritability
Investigations: bone density decreased
Long exposure (6 to 12 months): diabetes mellitus, glucose tolerance impaired,
total cholesterol increased, LDL increased, triglycerides increased, osteoporosis.
System Organ Class
Preferred Term
Infections and
infestations
Infection
Rhinitis
Post Marketing
Frequency
Frequency
Not known
Uncommon
Urinary tract infection
Not known
Angina pectoris
Uncommon
Not known
Ventricular
extrasystoles
Uncommon
Respiratory, thoracic
and mediastinal
disorders
Gastrointestinal
disorders
Not known
Bradycardia
Not known
Sudden cardiac death
Not known
Hot flushes
Very common
Vasodilatation
Very common
Angiopathy
Uncommon
Skin and
subcutaneous tissue
disorders
Thrombosis
Not known
Hypotension
Not known
Varicose vein
Not known
Not known
Pulmonary fibrosis
Not known
Inflammation
dehydrogenase
increased/ALT
Aspartate
aminotransferase
increased/AST
Common
Gammaglutamyltransferase
increased
Uncommon
Electrocardiogram
abnormal
Not known
ECG signs of
myocardial ischemia
Not known
Liver function test
abnormal
Not known
Platelet count
decreased
Uncommon
Uncommon
Prothrombin time
prolonged
Not known
Activated partial
thromboplastin time
prolonged
Not known
Cardiac murmur
Not known
Low density
lipoprotein increased
Not known
Blood triglycerides
increased
Not known
Not known
Haemoptysis
Uncommon
Not known
Blood bilirubin
increased
Emphysema
Uncommon
Cough
Not known
Reticulocyte count
increased
Pleural effusion
Not known
Lung infiltration
Not known
Respiratory disorder
Not known
Sinus congestion
Not known
Pulmonary embolism
Not known
Interstitial lung
disease
Not known
Not known
Common
Not known
Vomiting
Common
Not known
Gastrointestinal
haemorrhage
Not known
Abdominal distention
Not known
Not known
Dysphagia
Not known
Dry mouth
Not known
Duodenal ulcer
Not known
Gastrointestinal
disorder
Not known
Peptic ulcer
Not known
Rectal polyp
Not known
Hepatic function
abnormal
Not known
Jaundice
Not known
Alopecia
Uncommon
Injury, poisoning
and procedural
complications
Not known
Changes in Bone Density
In controlled clinical studies, patients with endometriosis (six months of therapy)
or uterine fibroids (three months of therapy) were treated with leuprorelin depot
3.75 mg. In endometriosis patients, vertebral bone density as measured by dual
energy x-ray absorptiometry (DEXA) decreased by an average of 3.9% at six months
compared with the pretreatment value. For those patients who were tested at six
or twelve months after discontinuation of therapy, mean bone density returned to
within 2% of pretreatment. When leuprorelin depot 3.75 mg was administered for
three months in uterine fibroid patients, vertebral trabecular bone mineral density
as assessed by quantitative digital radiography (QDR) revealed a mean decrease of
2.7% compared with baseline. Six months after discontinuation of therapy, a trend
toward recovery was observed.
Table 2: Women Indications
ADRs
Endo
(3.75 mg)
System Organ
Class
Dry skin
Not known
Infections and
infestations
Photosensitivity
reaction
Not known
Uncommon
Uncommon
Fibroids
(3.75 mg)
Not known
Infection
Uncommon
Rhinitis
Not known
Uncommon
Uncommon
Pyelonephritis
Uncommon
Furuncle
Uncommon
Not known
Urinary tract infection
Hair growth
abnormal
Not known
Vulvovaginal
candidiasis
Uncommon
Influenza
Uncommon
Uncommon
Common
Night sweats
Uncommon
Pigmentation disorder
Not known
Skin lesion
Uncommon
Myalgia
Uncommon
Bone swelling
Not known
Not known
Arthropathy
Not known
Arthralgia
Common
Muscular weakness
Uncommon
Pain in extremity
Uncommon
Not known
Not known
Nasopharyngitis
Neoplasms
benign,
malignant and
unspecified
(incl cysts and
polyps)
Not known
Not known
Pneumonia
Not known
Bone pain
Common
Pharyngitis
Not known
Post
Marketing
Frequency Frequency Frequency Frequency
Dermatitis
Pruritus
BC
(3.75 mg)
Preferred Term
Upper respiratory tract
infection
Common
Hair disorder
Endometriosis
In two clinical trials treating endo
Acetate for Depot Suspension wi
the following adverse reactions
probable relationship to study dru
in 5% or more of the patients re
not drug related are excluded.
Women
Table 2 presents ADRs and frequencies (very common [≥1/10]; common [≥1/100 to
<1/10]; uncommon [≥1/1,000 to <1/100]; not known [unable to estimate frequency
based upon available data]) from endometriosis, uterine fibroid and breast cancer
clinical studies and post-marketing experience. A blank indicates that the ADR was
not seen from that particular source.
Cases of serious venous and arterial thromboembolism have been reported, including
deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, and transient
ischemic attack. Although a temporal relationship was reported in some cases, most
cases were confounded by risk factors or concomitant medication use. It is unknown
if there is a causal association between the use of GnRH agonist and these events.
Not known
Rash
Rash maculo-papular
Endometriosis/Uterine Fibroid
Estradiol levels may increase duri
injection, but then decline to me
in estradiol can be associated wit
symptoms (see WARNINGS).
Uncommon
Spinal fracture
Not known
Not known
In this same study, the following
than 5% of the patients on Leup
Cardiovascular System - angina
System - anorexia, diarrhea; End
decrease; Musculoskeletal
Central/Peripheral Nervous
Respiratory System - hemoptysi
local skin reactions, hair growth; U
urgency, hematuria, testicular pain
hard nodule in throat, increased
acid.
Not known
Not known
Not known
Cardiovascular System
Edema
Gastrointestinal System
Nausea/vomiting
Endocrine System
Decreased Testicular Size*
Hot Flashes/sweats*
Impotence*
Central/Peripheral Nervous S
General Pain
Respiratory System
Dyspnea
Miscellaneous
Asthenia
*Physiologic effect of decreased
Not known
White blood cell
count decreased
Not known
ADVERSE REACTIONS
Prostate Cancer
In the majority of patients testos
during the first week, declining th
the end of the second week of tr
Potential exacerbations of signs an
of treatment is a concern in pati
urinary obstruction or hematur
neurological problems such as te
of the lower limbs or worsening o
In a clinical trial of Leuprorelin Acet
adverse reactions were reported to
to drug as ascribed by the trea
patients receiving the drug. Oft
patients with metastatic prostate
related are excluded.
T
MOST COMMON
(Intention T
Not known
White blood cell
count increased
Uncommon
Ecchymosis
Uncommon
Protein urine present
Common
Common
Not known
Nursing Mothers
increased
Alanin
It is not known whether leuprorelin
acetate isUncommon
excreted in human milk.
aminotransferase
Therefore, it should be administered
with caution to a nursing mother.
Epistaxis
Nausea
Not known
Pregnancy
Pelvic fibrosis
Not known
Leuprorelin
Acetate for Depot
Suspension is contraindicated
in women
Investigations
Haemoglobin
Uncommon
who are or may becomedecreased
pregnant while receiving the drug. When
administered on day six of Blood
pregnancy
at test dosages of 0.00024, 0.0024
urea increased Uncommon
Not known
and 0.024 mg/kg (1/600 to 1/6 the human dose) to rabbits, it produced
Blood
uric
acid
UncommonSimilar studies
Not known
a dose-related increase inincreased
major fetal abnormalities.
in
rats failed to demonstrate an increase in fetal malformations. There was
Blood
creatinine fetal weights with the twoNot
known
increased fetal mortality and
decreased
higher
increased
doses of the monthly formulation of leuprorelin acetate in rabbits and
Blood calcium
Uncommon
Not known
with the highest dose in rats.
increased
The effects on fetal mortality
are
logical
consequences
of
the
alterations
Common
Blood alkaline
in hormonal levels broughtphosphatase
about by this drug. Therefore, the possibility
increased may occur if the drug is administered
exists that spontaneous abortion
during pregnancy.
Very common
Blood lactic
Dyspnoea
Constipation
Uncommon
Carcinogenesis, Mutagenesis, Impairment of Fertility
Fatigue
Common
A two-year carcinogenicity
study was conducted
in rats and mice. In
Pyrexia
Not known
rats, a dose-related increase
of benign pituitary hyperplasia and benign
pituitary adenomas wasInjection
notedsite
at reaction
24 months when the drug
Notwas
known
administered subcutaneously
at high
(0.6 to 4 mg/kg).Not
There
Injection
site daily doses
Uncommon
known
was a significant but notinflammation
dose-related increase of pancreatic islet-cell
adenomas in females and Injection
of testicular
interstitial
cell adenomas inNot
males
site pain
Common
known
(highest incidence in the low dose group). In mice, no leuprorelin acetateInjection site
Common
Not known
induced tumors or pituitary
abnormalities were observed at a dose as
induration
high as 60 mg/kg for two years. Patients have been treated with leuprorelin
Injection site
Uncommon
acetate for up to three years
with doses as high as 10 mg/day and for
erythema
two years with doses as high as 20 mg/day without demonstrable pituitary
Injection site abscess
Not known
abnormalities.
sterile
Mutagenicity studies have Injection
been performed
with leuprorelin acetateNot
using
site
known
bacterial and mammalianhematoma
systems. These studies provided no evidence
of a mutagenic potential.Injection site irritation Uncommon
Clinical and pharmacologicChills
studies in adults with
leuprorelin acetate
Uncommon
Not and
known
similar analogs have shown
full reversibility of fertility suppressionNot
when
Nodule
known
the drug is discontinued after continuous administration for periods of
Thirst
Not
known
up to 24 weeks.
Uncommon
Pleural rub
Hyperhidrosis
Renal and urinary
disorders
Asthenia
Not known
Not known
Urticaria
Musculoskeletal and
connective tissue
disorders
Penile swelling
Not known
Drug/Laboratory Test Interactions
Penis
disorder
Not known
Administration of leuprorelin
acetate
depot in women results in suppression
of the pituitary gonadal Prostatic
system.pain
Normal function is usually restored
Not known
withinGeneral
threedisorders
months
depot treatment
is
Pain leuprorelin acetate
Common
Not known
andafter
discontinued.
Therefore,
diagnostic tests of pituitary gonadotropic and
administration
site
Chest
pain
Uncommon
conditions
gonadal
functions conducted during treatment and for up to three
Oedemaof leuprorelin acetate depot may
Not known
months after discontinuation
be
Oedema peripheral
Common
misleading.
Not known
Uncommon
Not known
Blood potassium
decreased
Phlebitis
Diarrhea
Hepato-biliary
disorders
Breast tenderness
Drug Interactions
Erectile dysfunction
Common
No pharmacokinetic-based
drug-drug
been
Testicular
atrophy interaction
Commonstudies haveNot
known
conducted with Leuprorelin Acetate Depot Suspension. However, because
Testicular pain
Not known
leuprorelin acetate is a peptide that is primarily degraded by peptidase
Breastenzymes
enlargement
Uncommon
and not by cytochrome P-450
as noted
in specific studies, and
Breast
pain to plasma proteins, drug interactions
Not known
the drug is only about 46%
bound
would not be expected toTesticular
occur. disorder
Not known
Not known
Tachycardia
Poor peripheral
circulation
Table 1: Prostate Cancer
Prostate Cancer
3.75 mg
Not known
Lymphoedema
Clinical and Postmarketing
The following sections present adverse events seen in clinical studies or postmarketing
experience. They are arranged by patient populations: Men, Women.
Men
Prostate Cancer
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.
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 or
hematuria which, if aggravated, may lead to neurological problems such as temporary
weakness and/or paresthesia of the lower limbs or worsening of urinary symptoms
(see WARNINGS AND PRECAUTIONS).
Table 1 presents all adverse drug reactions (ADR) and frequencies (very common
[≥1/10]; common [≥1/100 to <1/10]; uncommon [≥1/1,000 to <1/100]; not known
[unable to estimate frequency based upon available data]) from prostate cancer
clinical studies and post marketing experience. A blank indicates that the ADR was
not seen from that particular source.
Uncommon
Hypertension
Endometriosis/Uterine Fibroids
Since bone loss can be anticipated as part of natural menopause, it may
also be expected to occur during a medically-induced hypoestrogenic
Prostate
Cancer
PostofMarketing
state. Bone loss has been found to be reversible
after
completion
a
3.75 mg
six month course of leuprorelin acetate.
System Organ Class Preferred Term
Frequency
Frequency
Experience with Leuprorelin Acetate for Depot Suspension in females
has been
limited to women
18 years of ageUncommon
and older, treatedNotfor
6
Reproductive system
Gynaecomastia
known
months.
and breast disorders
Not known
Myocardial infarction
The following adverse events are commonly associated with the pharmacological
actions of leuprorelin acetate on the steroidogenesis:
Men
Neoplasm benign, malignant and unspecified (including cysts and polyps):
prostate tumor flare, aggravation of prostate cancer
Metabolism and nutrition disorders: weight gain, weight loss
Psychiatric disorders: loss of or decreased libido, increased libido
Nervous system disorders: headache, muscular weakness
Vascular disorders: vasodilatation, hot flushes, hypotension, orthostatic hypotension
Skin and subcutaneous tissue disorders: dry skin, hyperhidrosis, rash, urticaria,
hair growth abnormal, hair disorder, night sweats, hypotrichosis, pigmentation
disorder, cold sweat, hirsutism
Reproductive system and breast disorders: gynaecomastia, breast tenderness,
erectile dysfunction, testicular pain, breast enlargement, breast pain, prostate pain,
penile swelling, penis disorder, testis atrophy
General disorders and administration site conditions: mucosal dryness
Investigations: PSA increased, bone density decreased
Long exposure (6 to 12 months): diabetes mellitus, glucose tolerance impaired,
total cholesterol increased, LDL increased, triglycerides increased, osteoporosis.
Cardiac failure
congestive
Arrhythmia
ADVERSE REACTIONS
Men
Prostate Cancer
Initially, leuprorelin acetate, 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 Leuprorelin Acetate for Depot Suspension 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 ureteric obstruction
and spinal cord compression have been observed, which may contribute to paralysis
with or without fatal complications. Worsening of symptoms may contribute to
paralysis with or without fatal complications.
six months. Therapy may be preoperative prior to myomectomy or
hysterectomy, or it may provide symptomatic relief for the perimenopausal
woman who does not desire surgery.
Common
Skin cancer
Not known
Leukopenia
Blood and
lymphatic
Anaemia
system disorders
Iron deficiency
anaemia
Uncommon
Not known
Common
Ankylosing
spondylitis
Not known
Immune system
disorder
Anaphylactic reaction
Not known
Tenosynovitis
Not known
Not known
Not known
Endocrine
disorders
Goiter
Urinary incontinence
Metabolism
and nutrition
disorders
Anorexia
Dysuria
Uncommon
Pollakiuria
Uncommon
Pharyngitis
Not known
Micturition urgency
Pneumonia
Not known
Haematuria
Uncommon
Uncommon
Not known
Not known
Not known
Fungal skin infection
Uncommon
Urinary retention
Neoplasms benign,
malignant and
unspecified (incl cysts
and polyps)
Neoplasm
Uncommon
Bladder spasm
Not known
Urinary tract disorder
Not known
Skin cancer
Not known
Not known
Blood and lymphatic
system disorder
Anaemia
Not known
Urinary tract
obstruction
Immune system
disorder
Anaphylactic reaction
Not known
Polyuria
Uncommon
Pituitary apoplexy
Not known
Uncommon
Uncommon
Diabetes mellitus
Increased appetite
Not known
Uncommon Uncommon Very
common
Decreased appetite
Not known
Common
Hypoglycaemia
Not known
Dehydration
Not known
Hyperlipidaemia
Not known
Hypercholesterolaemia Common
Hyperphosphatemia
Not known
Hypoproteinemia
Not known
Endo
(3.75 mg)
System Organ
Class
Psychiatric
disorders
Preferred Term
Fibroids
(3.75 mg)
BC
(3.75 mg)
Frequency Frequency Frequency Frequency
Abnormal weight gain Very
common
Common
Abnormal loss of
weight
Common
Common
Very
common
Affect lability
Very
common
Common
Common
Uncommon
Nervousness
Very
common
Common
Libido decreased
Very
common
Common
Very
common
Common
Very
common
Libido increased
Sleep disorder
Nervous system
disorders
Major depression
Common
Anxiety
Common
Delusion
Uncommon
Thinking abnormal
Uncommon
Confusional state
Common
Euphoric mood
Uncommon
Hostility
Common
Apathy
Uncommon
Nervousness/anxiety
Very
common
Common
Not known
Common
Not known
Very
common
Not known
Suicide attempt
Not known
Common
Very
common
Not known
Skin discolouration
Uncommon
Uncommon
Pigmentation disorder
Uncommon Common
Arthropathy
Common
Common
Arthralgia
Common
Common
Very
common
Back pain
Common
Common
Very
common
Arthritis
Uncommon
Common
Neck pain
Common
Common
Common
Periarthritis
Common
Uncommon
Dysuria
Common
Pollakiuria
Uncommon
Not known
Not known
Uncommon
Hypertonia
Common
Common
Ataxia
Uncommon
Reproductive
system and
breast disorders
Not known
Common
Not known
Common
HOW SUPPLIED
Urinary tract
obstruction
Not known
Gynaecomastia
Not known
Breast tenderness
Not known
Vaginal haemorrhage
Not known
Common
Uncommon
Breast enlargement
Uncommon
Breast engorgement
Uncommon
Breast atrophy
Common
Genital discharge
Common
Common
Common
Uncommon
Transient ischemic
attack
Not known
Metrorrhagia
Paralysis
Not known
Menopausal
symptoms
Neuromyopathy
Not known
Vaginitis
Convulsion
Not known
Eye disorder
Uncommon
Not known
Visual impairment
Common
Not known
Amblyopia
Common
Not known
Eye pain
Uncommon
Conjunctivitis
Uncommon Common
Dry eye
Vertigo
Not known
Common
Tinnitus
Common
Not known
Hearing impaired
Not known
Cardiac failure
congestive
Not known
Arrhythmia
Not known
Myocardial infarction
Not known
Angina pectoris
Not known
Tachycardia
Uncommon Uncommon
Palpitations
Common
Vasodilatation
Very
common
Very
common
Uncommon Common
Common
Common
Chest pain
Common
Uncommon Common
Oedema
Common
Uncommon Common
Oedema peripheral
Common
Common
Common
Face oedema
Uncommon
Common
Very
common
Generalised oedema
Uncommon
Asthenia
Common
Uncommon
Injection site mass
Uncommon Uncommon
Injection site pain
Common
Not known
Injection site
induration
Very
common
Not known
Injection site pruritus
Common
Injection site erythema
Common
Common
Not known
Injection site
haemorrhage
Common
Phlebitis
Not known
Injection site
hematoma
Thrombosis
Not known
Chills
Hypotension
Not known
Nodule
Varicose vein
Not known
Uncommon
Pleural rub
Not known
Injection site
hypersensitivity
Common
Not known
Common
Common
Not known
Not known
Not known
Thirst
Common
Not known
Common
Not known
General physical
health deterioration
Very
common
Feeling hot
Very
common
Irritability
Common
Haemoptysis
Dysphonia
Not known
Common
Not known
Not known
Dyspnoea
Common
Very
common
Not known
Uncommon
Not known
Uncommon
Not known
Not known
Hypertension
Pulmonary fibrosis
Not known
Common
Lymphoedema
Epistaxis
Not known
Injection site abscess
sterile
Very
common
Not known
Common
Injection site
inflammation
Not known
Hot flush
Very
common
Pyrexia
Common
Bradycardia
Very
common
Fatigue
Not known
Not known
Not known
Malaise
Pleural effusion
Not known
Condition aggravated
Lung infiltration
Not known
Inflammation
Not known
Respiratory disorder
Not known
Pelvic fibrosis
Not known
Sinus congestion
Not known
Blood urea increased
Not known
Blood uric acid
increased
Not known
Cough
Common
Oropharyngeal pain
Common
Investigations
Common
Uncommon
Pulmonary embolism
Not known
Interstitial lung
disease
Not known
Blood creatinine
increased
Not known
Blood calcium
increased
Not known
Constipation
Common
Uncommon Common
Not known
Nausea
Very
common
Common
Very
common
Not known
Body temperature
increased
Uncommon Common
Not known
Electrocardiogram
abnormal
Not known
Not known
ECG signs of
myocardial ischemia
Not known
Not known
Liver function test
abnormal
Vomiting
Nausea and vomiting
Common
Uncommon
Gastrointestinal
haemorrhage
Abdominal distention
Uncommon
Diarrhoea
Common
Dyspepsia
Uncommon
Flatulence
Uncommon Common
Gastritis
Uncommon
Common
Common
Not known
Not known
Gingival bleeding
Uncommon
Dry mouth
Common
Uncommon
Abdominal pain
Common
Common
Not known
Common
Abdominal pain upper
Common
Abdominal pain lower
Common
Stomatitis
Common
Retching
Common
Uncommon
Common
Not known
Platelet count
decreased
Not known
Blood potassium
decreased
Not known
White blood cell
count increased
Not known
White blood cell
count decreased
Not known
Prothrombin time
prolonged
Not known
Activated partial
thromboplastin time
prolonged
Not known
Uncommon
Duodenal ulcer
Not known
Laboratory test
abnormal
Gastrointestinal
disorder
Not known
Cardiac murmur
Not known
Low density
lipoprotein increased
Not known
Blood triglycerides
increased
Not known
Not known
Blood bilirubin
increased
Not known
Hepatic function
abnormal
Not known
Injury, poisoning Spinal fracture
and procedural
complications
Not known
Serious liver injury
Not known
Abdominal discomfort
Common
Tongue disorder
Common
Peptic ulcer
Not known
Rectal polyp
Liver tenderness
Uncommon
Jaundice
Not known
Erythema
Common
Alopecia
Common
Ecchymosis
Common
Acne
Very
common
Seborrhoea
Common
Rash
Common
Rash maculo-papular
Uncommon
Dry skin
Common
Photosensitivity
reaction
Uncommon
Common
Not known
Common
Hyperhidrosis
Common
Not known
Common
Not known
Not known
Common
Uncommon
Common
OVERDOSAGE
There is no clinical experience with the effects of an acute overdose of leuprorelin
acetate depot suspension. In animal studies, doses of approximately 133 times the
recommended human dose resulted in dyspnea, decreased activity and local irritation
at the injection site. In cases of overdosage, the patients should be monitored closely
and management should be symptomatic and supportive.
DOSAGE AND ADMINISTRATION
Urticaria
Skin odour abnormal
Not known
License Holder
Common
Pain
Injection site reaction
Takeda Japan, for Abbott Laboratories, Spain
Not known
Uncommon Common
Menorrhagia
General
disorders and
administration
site conditions
Manufacture
The format of this leaflet was determined by the Ministry of Health and its content
was checked and approved.
Pelvic pain
Not known
Not known
Leuprorelin Acetate Prefilled Dual Chamber Syringe (PDS) 3.75 mg - is available in a
single dose administration kit of a syringe containing sterile lyophilized microspheres
which are leuprorelin acetate incorporated in a biodegradable polymer of polylactic
acid. When mixed with 1 mL of diluent leuprorelin acetate is administered as a single
intramuscular or subcutaneous injection.
Abbott Medical Laboratories Ltd., P.O.B. 58099, Tel-Aviv 61580, Israel
Not known
Common
STORAGE
Not known
Uncommon
Vision blurred
Leuprorelin Acetate Prefilled Dual Chamber Syringe (PDS):
For optimal performance of the Prefilled Dual Chamber Syringe (PDS), read and follow
the following instructions:
1.To prepare for injection, screw the white plunger into the end stopper until the
stopper begins to turn.
2.Hold the syringe UPRIGHT. Release the diluent by SLOWLY PUSHING (6 to 8 seconds)
the plunger until the first stopper is at the blue line in the middle of the barrel.
3.Keep the syringe UPRIGHT. Gently mix the microspheres (particles) thoroughly to
form a uniform suspension. The suspension will appear milky.
4.Hold the syringe UPRIGHT. With the opposite hand pull the needle cap upward
without twisting.
5.Keep the syringe UPRIGHT. Advance the plunger to expel the air from the
syringe.
6.Inject the entire contents of the syringe intramuscularly or subcutaneously at the time
of the reconstitution. The suspension settles very quickly following reconstitution;
therefore, leuprorelin acetate should be mixed and used immediately.
NOTE: Aspirated blood would be visible just below the luer lock connection if a
blood vessel is accidentally penetrated. If present, blood can be seen through the
transparent hub of the needle.
Not known
Common
Loss of consciousness
Use in Treatment of Uterine Fibroids
Recommended duration of therapy is up to 6 months.
Urinary tract disorder
Breast pain
Not known
Use in Treatment of Endometriosis
It is recommended that the therapy begins with the first day of the menstrual cycle
after pregnancy has been ruled out. Development of amenorrhea is usually evidence
of a clinical response, although spotting or bleeding from the atrophic endometrium
can still occur.
Therapy should be continued uninterrupted for 6 months.
Bladder spasm
Galactorrhoea
Cerebrovascular
accident
Endometriosis
Uterine fibroids
Prostate cancer
Breast cancer
Not known
Common
Menstrual disorder
Neuropathy peripheral
Not known
Not known
Dysmenorrhea
Common
Convulsions local
Not known
Hematuria
Uncommon
Indication
3.75
Store below 25°C. Once reconstituted with the sterile diluent, the suspension should
be administered immediately.
Protect from freezing.
Not known
Common
Not known
Urinary incontinence
Nocturia
Migraine
Not known
Micturition urgency
Not known
Not known
Common
Musculoskeletal
stiffness
Not known
Uncommon
Not known
Muscular weakness
Common
Syncope
Not known
Not known
Nuchal rigidity
Dose (mg)
Preparation for Administration
Common
Uncommon Uncommon
Tenosynovitis
Common
Not known
Not known
Bone pain
Common
Uncommon
Common
Dermatitis bullous
Common
Uncommon
Not known
Uncommon
Myalgia
The recommended dose of Leuprorelin Acetate for Depot Suspension is summarized
below:
Uncommon
Nail disorder
Paraesthesia
Tremor
Skin and
subcutaneous
tissue disorders
Uncommon
Not known
Hypoaesthesia
Hepato-biliary
disorders
Common
Very
common
Dysgeusia
Gastrointestinal
disorders
Hirsutism
Hair disorder
Very
common
Amnesia
Respiratory,
thoracic and
mediastinal
disorders
Not known
Very
common
Memory impairment
Vascular
disorders
Not known
Hair growth abnormal
Headache
Somnolence
Cardiac
disorders
Dermatitis
Ankylosing spondylitis
Renal and
urinary
disorders
Post
Marketing
Frequency Frequency Frequency Frequency
Bone swelling
Common
Lethargy
Ear and
labyrinth
disorders
Musculoskeletal
and connective
tissue disorders
Not known
Not known
Very
common
BC
(3.75 mg)
Skin lesion
Not known
Suicide ideation
Dizziness
Preferred Term
Fibroids
(3.75 mg)
Night sweats
Not known
Very
common
Uncommon Common
Dizziness postural
Eye disorders
Not known
Not known
Very
common
System Organ
Class
Very
common
Very
common
Personality disorder
Depression
Endo
(3.75 mg)
Pruritus
Mood swings
Insomnia
Post
Marketing
Common
Very
common
Not known
General
Leuprorelin Acetate for Depot Suspension - 1 Month 3.75 mg must be administered
under the supervision of a physician.
As with other drugs administered by injection, the injection sites should be varied
periodically.
Upon reconstitution, the suspension should be discarded if not used immediately.
Administration Guidelines
Reconstitute the microspheres immediately prior to administration and administer as
a single intramuscular or subcutaneous injection once a month.
SH LUC PDS 3.75 API Apr 2012