Eligard 3 Month

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Leuprorelin acetate 22.5 mg (includes 28.2mg leuprorelin acetate to deliver 22.5mg leuprorelin);  ;  ; Leuprorelin acetate 22.5 mg (includes 29.2mg leuprorelin acetate to deliver 22.5mg leuprorelin)
Available from:
Mundipharma New Zealand Ltd
INN (International Name):
Leuprorelin acetate 22.5 mg (includes 28.2mg leuprorelin acetate to deliver 22.5mg leuprorelin)
Dosage:
22.5 mg
Pharmaceutical form:
Injection with diluent
Composition:
Active: Leuprorelin acetate 22.5 mg (includes 28.2mg leuprorelin acetate to deliver 22.5mg leuprorelin)     Excipient: N-Methyl-2-pyrrolidone Polyglactin Active: Leuprorelin acetate 22.5 mg (includes 29.2mg leuprorelin acetate to deliver 22.5mg leuprorelin) Excipient: N-Methyl-2-pyrrolidone Polyglactin
Units in package:
Syringe, Kit (Syringe A & B, replacement plunger+needle), 1 dose unit
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Hemmo Pharmaceuticals Pvt. Ltd.
Therapeutic indications:
indicated for the palliative treatment of advanced prostate cancer.
Product summary:
Package - Contents - Shelf Life: Syringe, Kit (Syringe A & B, replacement plunger+needle) - 1 dose units - 24 months from date of manufacture stored at 2° to 8°C (Refrigerate, do not freeze) 8 weeks not refrigerated stored at or below 25°C 30 minutes reconstituted stored at or below 25°C - Syringe, PP Syringe A - 1 dose units -   - Syringe, PP Syringe B - 1 dose units -  
Authorization number:
TT50-7152a
Authorization date:
2003-10-22

Data Sheet

Version 9.0

ELIGARD

®

NAME OF THE MEDICINE

Leuprorelin

acetate

CAS: 74381-53-6

DESCRIPTION

Eligard

is a sterile polymeric matrix formulation of leuprorelin acetate for subcutaneous injection. It

is designed to deliver leuprorelin acetate at a controlled rate over a therapeutic period.

Leuprorelin acetate is a synthetic nonapeptide analogue of naturally occurring gonadotropin releasing

hormone (GnRH or LH-RH) that, when given continuously, inhibits pituitary gonadotropin secretion

and suppresses testicular steroidogenesis.

The analogue 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).

Composition

Eligard

is available in a single use kit. The kit consists of a two-syringe mixing system, a 20-gauge

5/8 inch needle (for Eligard

1 month and Eligard

3 month and Eligard® 4 month) or a or a 18-gauge

5/8-inch needle (for Eligard

6 month), a silicone desiccant pouch to

control moisture uptake, and

package insert for constitution and administration procedures. Each

syringe is individually packaged.

One contains the Atrigel

Delivery System and the other contains

leuprorelin acetate.

Eligard

is prefilled and supplied in two separate, sterile syringes whose contents are mixed

immediately prior to administration. The two syringes are joined and the single dose product is

mixed

until it is homogenous. Eligard

is administered subcutaneously where it forms a solid drug

delivery

depot.

The Atrigel

Delivery System is a polymeric (non-gelatin containing) delivery system consisting of a

biodegradable polyglactin. The

polymer

is dissolved

biocompatible solvent,

N

-methyl-2-

pyrrolidone. The polyglactin mixture and volume differ with each presentation of Eligard

Data Sheet

Version 9.0

Eligard

contains no anti-microbial agent Eligard

does not contain: lactose, sucrose, gluten, tartrazine, or

any other azo dyes.

Eligard

1 month contains 10.6 mg of lyophilised leuprorelin acetate. Eligard

1 month delivers 7.5

mg of

leuprorelin acetate (equivalent to approximately 7.0 mg leuprorelin free base) dissolved in 160

N

methyl-2-pyrrolidone and 82.5 mg polyglactin. The approximate weight of the administered

formulation

is 250 mg. It is designed to deliver 7.5 mg of leuprorelin acetate at a controlled rate over

a 1 month

therapeutic period.

Eligard

3 month contains 29.2 mg lyophilised leuprorelin acetate. Eligard

3 month delivers

22.5 mg of leuprorelin acetate (equivalent to approximately 21 mg leuprorelin free base) dissolved in

193.9 mg

N

-methyl-2-pyrrolidone and 158.6 mg polyglactin. The approximate weight of the

administered

formulation is 375 mg. It is designed to deliver 22.5 mg of leuprorelin acetate at a

controlled rate over a 3

month therapeutic period.

Eligard

4 month contains 37.2 mg lyophilised leuprorelin acetate.

Eligard

4 month delivers 30 mg

leuprorelin acetate (equivalent to approximately 28 mg leuprorelin free base) dissolved in

258.5

N

-methyl-2-pyrrolidone and 211.5 mg polyglactin.

The approximate weight of the

administered formulation is 500 mg. It is designed to deliver 30 mg of leuprorelin acetate at a

controlled rate over a 4 month therapeutic period.

Eligard

6 month contains 59.2 mg of lyophilised leuprorelin acetate. Eligard

6 month delivers

45 mg

of leuprorelin acetate (equivalent to approximately 42 mg leuprorelin free base) dissolved in

165 mg

N

methyl-2-pyrrolidone and 165 mg polyglactin. The approximate weight of the

administered formulation

is 375 mg. It is designed to deliver 45 mg of leuprorelin acetate at a

controlled rate over a 6 month

therapeutic period.

USES

Actions

Leuprorelin acetate, an LH-RH agonist, acts as a potent inhibitor of gonadotropin secretion when

given

continuously in therapeutic doses.

Animal and human studies indicate that after an initial

stimulation,

chronic administration of leuprorelin acetate results in suppression of testicular

steroidogenesis. This effect

is reversible upon discontinuation of drug therapy.

Administration of leuprorelin acetate has resulted in inhibition of the growth of certain hormone-

dependent tumours (prostatic tumours in Noble and Dunning male rats and DMBA-induced

mammary

tumours in female rats) as well as atrophy of the reproductive organs.

In humans, administration of leuprorelin acetate results in an initial increase in circulating levels

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

oestrone and

oestradiol in premenopausal females).

However, continuous administration of

leuprorelin acetate

results in decreased levels of LH and FSH. In males, testosterone is reduced

to below castrate

threshold (

50 ng/dL). These decreases occur within two to six weeks after

initiation of treatment. Long-term studies have shown that continuation of therapy with leuprorelin

acetate maintains testosterone below the castrate level for up to seven years. Tumour size was not

measured directly during the clinical trial program, but there was an indirect beneficial tumour

response as shown by a reduction in prostate-specific antigen (PSA) values (see Table A).

Table A. Effect on Eligard

on Patient Serum PSA Values

Data Sheet

Version 9.0

Eligard

7.5 mg

22.5 mg

40 mg

45 mg

Mean PSA Reduction at Study Conclusion

Patients with Normal PSA at Study Conclusion*

Leuprorelin acetate is not active when given orally.

Pharmacokinetics

Absorption

The absorption pharmacokinetic parameters determined for Eligard

are presented in Table 1.

Table 1.

Absorption pharmacokinetic parameters for Eligard

®

Presentation

Cmax ± SD(ng/mL)

Tmax ± SD (hours)

Eligard

1 month

25.3

11.3

Eligard

3 month *

Eligard

3 month**

Eligard

4 month *

Eligard

4 month**

Eligard

6 month

102.4

72.1

4.75

* first dose

** second dose

After the initial increase following each injection, mean serum concentrations remained relatively

constant; 0.28 – 2.0 ng/mL for Eligard

1 month, 0.2 – 2.0 ng/mL for Eligard

month, 0.1 – 1.0 ng/mL for Eligard

4 month and 0.2 – 2.0 ng/mL for Eligard

6 month. There

was no evidence of significant accumulation during repeated dosing. Nondetectable leuprorelin

plasma

concentrations

have

been

observed

during

chronic

Eligard

administration,

testosterone levels were maintained at castrate levels.

Distribution

mean

steady-state

volume

distribution

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 3

hours based on a two compartment model.

Drug metabolism studies were not conducted with Eligard

. Upon administration with different

leuprorelin acetate formulations, the major metabolite of leuprorelin acetate is a pentapeptide (M-

1) metabolite.

Excretion

Data Sheet

Version 9.0

Drug excretion studies were not conducted with Eligard

Special Populations

Geriatrics

The majority of the patients (approximately 70%) studied in these clinical trials were age 70 and

older.

Paediatrics

The safety and effectiveness of Eligard

in paediatric patients have not been established (see

CONTRAINDICATIONS).

Renal and Hepatic Insufficiency

The pharmacokinetics of Eligard

in hepatically and renally impaired patients have not been

determined.

CLINICAL STUDIES

In the open-label, multicentre studies conducted with Eligard

patients with advanced

prostate cancer were treated with monthly injections of Eligard

1 month for 6 months, a

single injection of Eligard

3 month, given once every three months for 6 months, a single

injection of Eligard

4 month, given once every four months for 8 months or a single injection

of Eligard

6 month, given once every six months for 12 months. Patient stages in the open-

label, multicentre studies are described in Table 2. The Eligard

1 month and Eligard

month studies evaluated the achievement and maintenance of serum testosterone suppression

over six months of therapy. The Eligard

4 month study evaluated the

achievement and

maintenance of serum testosterone suppression over eight months of

therapy. The Eligard

6 month study evaluated the achievement and maintenance of serum

testosterone suppression over twelve months of therapy.

Table 2.

Description of patients in open-label, multicentre studies for

Eligard

®

Presentation

Total

Stage A disease

Stage B disease

Stage C disease

Stage D disease

Eligard

1 month

Eligard

3 month

Eligard

4 month

Eligard

6 month

Patients with brain metastases, spinal cord compression and/or urinary tract obstruction,

serum testosterone levels below 150 ng/dL at screening, uncontrolled congestive heart failure,

myocardial infarction or a coronary vascular procedure, symptomatic cardiovascular disease,

venous thrombosis, uncontrolled hypertension, symptomatic hypotension, insulin dependent

diabetes, a history of drug and alcohol abuse, other serious intercurrent illness, (for example,

haematological, renal hepatic, respiratory, endocrine) were excluded from the studies.

Data Sheet

Version 9.0

Serum

Testosterone

Concentration

(ng/dL)

Eligard

1 month

The mean testosterone concentration increased from 361.3 ng/dL at baseline to 574.6 ng/dL

following

initial

subcutaneous

injection.

mean

serum

testosterone

concentration then decreased to below baseline by day 10 and was 21.8 ng/dL on day 28. At

the conclusion of the study (month 6), mean testosterone concentration was 6.1 ng/dL (Figure

1a),

comparable to levels following bilateral orchiectomy

Serum testosterone was suppressed to below the castrate threshold

50 ng/dL) by day 28

(week 4) in 112 of 119 (94.1%) patients remaining in the study. The remaining seven patients

all attained the castrate threshold by day 42.

A high proportion of patients (97% at day

42), achieved testosterone suppression levels of ≤ 20 ng/dL, although the full

benefit of

these low levels has not yet been established.

Once testosterone suppression at or below

serum concentrations of 50 ng/dL was achieved, no patients (0%) demonstrated breakthrough

(concentration above 50 ng/dL) at any time in the study.

All 117 evaluable patients in the

study at month 6 (two patients withdrew for reasons unrelated to drug) had testosterone

concentrations of

50 ng/dL.

Figure 1a.

Eligard

®

1 month mean serum testosterone concentrations

(n = 117)

Injection

Injection #2

Injection #3

Injection #4

Injection #5

Injection #6

Months Post Baseline

Data Sheet

Version 9.0

Serum Testosterone Concentration (ng/dL)

Eligard

3 month

The mean testosterone concentration increased from 367.1 ng/dL at baseline to 588.0 ng/dL

following

initial

subcutaneous

injection.

mean

serum

testosterone

concentration then decreased to below baseline by day 14 and was 27.7 ng/dL on day 21. At

the conclusion of the study (month 6), mean testosterone concentration was 10.1 ng/dL

(Figure 1b),

comparable to levels following bilateral orchiectomy.

Of the original 117 patients, one received less than a full dose of Eligard

3 month at baseline,

never suppressed, and was withdrawn at day 73 and given an alternate treatment. In

remaining 116 patients who did receive the full dose at baseline, serum testosterone was

suppressed to below the castrate threshold

50 ng/dL) by day 28 (week 4) in 115 of 116

(99%).

By day 35, all 116 patients (100%) who received a full dose at baseline attained the

castrate threshold.

A high proportion of patients (84% at day 28 and 92% at day 42),

achieved testosterone suppression levels of ≤ 20 ng/dL, although the full benefit of these

low levels has not yet been established

Once testosterone suppression at or below serum

concentrations of 50 ng/dL was achieved, only one patient (<1%) demonstrated breakthrough

(concentration above 50 ng/dL) following initial injection; that patient remained below the

castrate threshold following the second injection.

All 111 evaluable patients in the study at

month 6 had testosterone concentrations of

50 ng/dL.

Figure 1b.

Eligard

®

3 month mean serum testosterone concentrations

(n = 111)

Injection

Injection #2

Months Post Baseline

Data Sheet

Version 9.0

Serum Testosterone Concentration (ng/dL)

Eligard

4 month

The mean testosterone concentration increased from 385.5 ng/dL at baseline to 610.0 ng/dL

following

initial

subcutaneous

injection.

mean

serum

testosterone

concentration then decreased to below baseline by day 14 and was 17.2 ng/dL on day 28. At

the conclusion of the study (month 8), mean testosterone concentration was 12.4 ng/dL

(Figure 1c),

comparable to levels following bilateral orchiectomy.

Serum testosterone was suppressed to below the castrate threshold

50 ng/dL) by day 28 in

85 of 89 (96%) patients remaining in the study.

All 89 (100%) of patients remaining in the

study attained the castrate threshold by day 42.

A high proportion of patients (67% at day

28 and 90% at day 42), achieved testosterone suppression levels of ≤ 20 ng/dL, although

the full benefit of these low levels has not yet been established

Once testosterone

suppression at or below serum concentrations of 50 ng/dL was achieved, three patients (3%)

demonstrated breakthrough (concentration above 50 ng/dL) during the study. These patients

again reached castrate suppression following the second injection of study drug.

Of 82

evaluable patients in the study at month 8, 81 had testosterone concentrations of

50 ng/dL.

Figure 1c.

Eligard

®

4 month mean serum testosterone concentrations (n =

90)

1 00

I n j e c t i o n # 2

M o n t h s P o s t B a s e l i n e

Eligard

6 month

The mean testosterone concentration increased from 367.7 ng/dL at baseline to 588.6 ng/dL

following

initial

subcutaneous

injection.

mean

serum

testosterone

concentration then decreased to below baseline by day 14 and was 16.7 ng/dL on day 28. At

the conclusion of the study (month 12), mean testosterone concentration was 12.6 ng/dL

(Figure 1d),

comparable to levels following bilateral orchiectomy

Data Sheet

Version 9.0

Serum Testosterone

Concentration (ng/dL)

Serum testosterone was suppressed to below the castrate threshold

50 ng/dL) by day 28 in

108 of 109 (99%) patients remaining in the study. One patient (<1%) did not achieve castrate

suppression and was withdrawn from the study on day 85.

A high proportion of patients

remaining in the study (84% at day 28 and 95% at day 42), achieved

testosterone

suppression levels of ≤ 20 ng/dL, although the full benefit of these low levels has not yet

been established.

Once testosterone suppression at or below serum concentrations of 50 ng/dL

was achieved, one patient (<1%) demonstrated breakthrough (concentration above 50 ng/dL)

during the study. This patient reached castrate suppression at day 21 and remained suppressed

until day 308 when his testosterone level rose to 112 ng/dL. At month 12, his testosterone was

210 ng/dL. Of 103 evaluable patients in the study at month

12, 102 had testosterone

concentrations of

50 ng/dL.

All five non-evaluable patients who had achieved castration by day 28 maintained castration

at each timepoint, up to and including the time of withdrawal.

Figure 1d.

Eligard

®

6 month mean serum testosterone concentrations (n =

103)

Injection #2

Months Post Baseline

Serum PSA decreased in all patients whose baseline values were elevated above the normal

limit.

Mean values were reduced 94% from baseline to month 6 for Eligard

1 month, 98%

from baseline to month 6 for Eligard

3 month, 86% from baseline to month 8 for Eligard

month and 97% from baseline to month 12 for Eligard

6 month.

At month 6, PSA levels had decreased to within normal limits in 94% of patients who presented

with elevated levels at baseline for Eligard

1 month. At month 6, PSA levels had decreased

to within normal limits in 91% of patients who presented with elevated levels at

baseline for

Eligard

3 month. At month 8, PSA levels had decreased to within normal limits in 93% of

patients who presented with elevated levels at baseline for Eligard

4 month. At

Data Sheet

Version 9.0

month 12, PSA levels had decreased to within normal limits in 95% of patients who presented

with elevated levels at baseline for Eligard

6 month.

Other secondary efficacy endpoints evaluated included WHO performance status, bone pain,

urinary pain and urinary signs and symptoms.

At baseline, 88% of patients using Eligard

1 month, 94% of patients using Eligard

3 month,

90% of patients using Eligard

4 month and 90% of patients using Eligard

6 month

were

classified as “fully active” by the WHO performance status scale (Status=0). Eleven percent

of patients using Eligard

1 month, 6% of patients using Eligard

3 month, 10% of patients

using Eligard

4 month and 7% of patients using Eligard

6 month were “restricted

strenuous activity but ambulatory and able to carry out work of a light or sedentary nature”

(Status=1). Three percent of patients using Eligard

6 month were classified as “ambulatory

but unable to carry out work activities” (Status 2).

These percentages were unchanged at month 6 for Eligard

1 month.

At month 6, 96% of

patients using Eligard

3 month, 87% of patients using Eligard

4 month at month 8 and 94%

of patients using Eligard

6 month at month 12 were classified as “fully active” by the WHO

performance status scale (Status=0). Four percent of patients using Eligard

3 month

month 6, 12% of patients using Eligard

4 month at month 8 and 5% of patients using

Eligard

6 month at month 12 were “restricted in strenuous activity but ambulatory and able

to carry out work of a light or sedentary nature” (Status=1).

One percent of patients using

Eligard

4 month at month 8 and 1% of patients using Eligard

6 month at month 12 were

“ambulatory but unable to carry out work activities” (Status 2).

At baseline and at month 6 for Eligard

1 month and Eligard

3 month, at month 8 for Eligard

4 month and at month 12 for Eligard

6 month, patients experienced little bone pain. Urinary

pain was also low both at baseline and at month 6, 8 or 12, respectively. Urinary signs and

symptoms were similarly low at baseline and decreased modestly for

Eligard

1 month,

Eligard

4 month, and Eligard

6 month at month 6, 8 or 12, respectively. Urinary signs and

symptoms were similarly low at baseline and increase modestly for Eligard

3 month at month

6. In addition, there was a reduction in patients with prostate abnormalities detected during

physical exam from 102 (85%) at Screening to 77 (64%) at month 6 for Eligard

1 month,

from 96 (82%) at Screening to 76 (65%) at month 6 for

Eligard

3 month, from 66 (73%) at Screening to 54 (60%) at month 8 for Eligard

4 month

and from 89 (80%) at Screening to 60 (58%) at month 12 for Eligard

6 month.

INDICATIONS

Eligard

is indicated for the palliative treatment of advanced prostate cancer.

CONTRAINDICATIONS

Eligard

is contraindicated in patients

with hypersensitivity to GnRH, GnRH agonist

analogues or any of the components of Eligard

. Anaphylactic reactions to synthetic GnRH

or GnRH agonist analogues have been reported in the literature.

Data Sheet

Version 9.0

Eligard

is contraindicated in women who are breastfeeding, pregnant or intending to become

pregnant and in paediatric patients. Eligard

was not studied in women or children. Moreover,

leuprorelin acetate can cause foetal harm when administered to a pregnant woman. Major foetal

abnormalities were observed in rabbits but not in rats after administration of leuprorelin acetate

throughout gestation. There were increased foetal mortality and decreased foetal weights in rats

and rabbits.

The effects on foetal mortality are

expected consequences of the alterations in

hormonal levels brought about by this drug.

The possibility exists that spontaneous abortion

may occur.

ELIGARD is contraindicated in patients who previously underwent orchiectomy (as with other

GnRH agonists, ELIGARD does not result in further decrease of serum testosterone in case of

surgical castration). ELIGARD is contraindicated as a sole treatment in prostate cancer patients

with spinal cord compression or evidence of spinal metastases.

PRECAUTIONS

Eligard

, like other LH-RH agonists, causes a transient increase in serum concentrations of

testosterone during the first week of treatment. Patients may experience worsening of

symptoms or onset of new signs and symptoms during the first few weeks of treatment,

including bone pain, neuropathy, haematuria, or bladder outlet obstruction.

Isolated cases of

ureteral obstruction and/or spinal cord compression, which may contribute to paralysis with or

without fatal complications, have been observed in the palliative treatment of advanced prostate

cancer using LH-RH agonists.

Initiating therapy with a non-steroidal anti-androgen at the same time as leuprorelin acetate

therapy has proven benefit in reducing flare reactions in 'at risk' patients (e.g. those with thecal

indentation, or at risk of cord compression, and patients with bladder neck

obstruction).

Additional administration of an appropriate antiandrogen should be considered beginning 3 days

prior to leuprolide therapy and continuing for the first two to three weeks of treatment. This has

been reported to prevent the sequelae of an initial rise in serum testosterone.

spinal

cord

compression

renal

impairment

develops,

standard

treatment

these

complications should be instituted.

General

Patients with metastatic vertebral lesions and/or with urinary tract obstruction should be closely

observed during the first few weeks of therapy.

Response to Eligard

should be monitored by measuring serum concentrations of testosterone

and prostate-specific antigen periodically.

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.

Following surgical castration, ELIGARD does not lead to a further decrease in serum

Data Sheet

Version 9.0

testosterone levels in male patients. A proportion of patients will have tumors which are not

sensitive to hormone manipulation. This is termed castrate-resistant prostate cancer. Signs

and/or

symptoms

tumor

progression

despite

adequate

testosterone

suppression

diagnostic of this condition. Current treatment paradigms recommend continued GnRH

therapy along with other therapeutic regimes for this circumstance.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Two-year carcinogenicity studies were conducted with leuprorelin acetate 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

mammalian systems and with Eligard

1 month in bacterial systems. These studies provided no

evidence of a genotoxic potential.

Use in pregnancy

(See CONTRAINDICATIONS)

Category D: Drugs which have caused, are suspected to have caused or may be expected to

cause, an increased incidence of human foetal malformations or irreversible damage. These

drugs may also have adverse pharmacological effects.

Although not relevant to the approved indication, leuprorelin acetate is contraindicated in

pregnancy due to its embryotoxic effects.

Use in lactation

Eligard

is contraindicated for use in breastfeeding women.

Paediatric Use

Eligard

is contraindicated in paediatric patients. It has not been studied in this population.

Geriatrics Use

The majority of the patients (approximately 70%) studied in the clinical trials were age 70 and

older.

Renally impaired patients

Eligard

was not studied in hepatically and renally impaired patients.

Interactions

Data Sheet

Version 9.0

There are no reports of drug interactions with leuprorelin acetate to date.

Effects on laboratory tests

In the majority of non-orchiectomised patients, testosterone levels increased during the first

week of treatment. They then decreased and by day 14 had returned to baseline levels or below.

Castrate levels were reached in 2 to 4 weeks. Once achieved, castrate levels were maintained as

long as the patient received their injections. Transient increases in acid phosphatase levels may

occur early in the treatment period; however, by the fourth week the elevated levels usually

decreased to values at or near normal. Therapy with leuprorelin results in suppression of the

pituitary-gonadal system. Results of diagnostic tests of pituitary gonadotropic and gonadal

functions conducted during and after leuprorelin therapy may be affected.

Effects on ability to drive and use machines

Presumed to be safe or unlikely to produce an effect on the ability to drive or use machinery.

Hyperglycemia and Diabetes

Hyperglycemia and an increased risk of developing diabetes have been reported in men

receiving LH-RH agonists. Hyperglycemia may represent development of diabetes mellitus or

worsening of glycemic control in patients with diabetes. Consideration should be given to

monitoring blood glucose and/or glycosylated hemoglobin (HbA1c) periodically in patients

receiving a LH-RH agonist.

Cardiovascular Diseases

Increased risk of developing myocardial infarction, sudden cardiac death and stroke has been

reported in association with the use of LH-RH agonists in men. The risk appears to be low based

but should be considered carefully along with all cardiovascular risk factors when determining a

treatment for patients with prostate cancer. Patients receiving a LH-RH agonist

should be

monitored for symptoms and signs suggestive of development of cardiovascular disease.

Effect on QT/QTc Interval

QT-prolongation has been observed during long-term androgen deprivation therapy. Physicians

should consider whether the benefits of androgen deprivation therapy outweigh the potential

risks in patients with congenital long QT syndrome, electrolyte abnormalities or

congestive

heart failure and in patients taking Class IA (e.g., quinidine, procainamide) or Class III (e.g.,

amiodarone, sotalol) antiarrhythmic medications.

Convulsions

Postmarketing reports of convulsions have been observed in patients on leuprorelin acetate

therapy. These included patients in the female and paediatric populations, patients with a history

of seizures, epilepsy, cerebrovascular disorders, central nervous system anomalies or tumours,

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.

Data Sheet

Version 9.0

ADVERSE EFFECTS

Eligard

, like other LH-RH analogues, caused a transient increase in serum testosterone

concentrations during the first two weeks of treatment.

Therefore, potential exacerbations of

signs and symptoms of the disease during the first few weeks of treatment are of concern in

patients with vertebral metastases and/or urinary obstruction or haematuria. If these conditions

are aggravated, it may lead to neurological problems such as weakness and/or paraesthesia of

the lower limbs or worsening of urinary symptoms (see PRECAUTIONS).

'Flare' Phenomenon:

The initial increase in circulating levels of pituitary gonadotropins and

gonadal steroids leads in some patients to a transient exacerbation of symptoms and signs

('flare' phenomenon). The exacerbation may include worsened bone pain, ureteric obstruction

and spinal cord compression. This possibility should be taken into account in deciding to

initiate leuprorelin acetate therapy in patients with existing obstructive uropathy or vertebral

metastases. Early symptoms of spinal cord compression such as paraesthesia should alert the

physician to the need for intensive monitoring and possible treatment.

There is no information available on the clinical effects of interrupting leuprorelin acetate

therapy and whether this will produce a withdrawal 'flare'.

Initiating therapy with a non-steroidal anti-androgen at the same time as leuprorelin acetate

therapy has proven benefit in reducing flare reactions in 'at risk' patients.

The safety of Eligard

was evaluated in open-label, multicentre studies. In Eligard

clinical

studies conducted, patient injection sites were closely monitored. The adverse reactions from

injections sites are summarised in Table 3.

Table 3.

Summary of adverse reactions from Eligard

®

injection sites

Presentation

Eligard

®

1

month

Eligard

®

3

month

Eligard

®

4

month

Eligard

®

6

month

Total number of injections (N=)

Adverse reactions (% of injections)

Transient burning/stinging

34.6

21.7

Pain

Erythema

Mild bruising

Pruritis

Induration

Ulceration

The majority (84%) of transient burning/stinging events for Eligard

1 month were reported

as mild. Pain was generally reported as brief in duration and mild in intensity. Erythema were

all reported as mild and generally resolved within a few days post-injection.

The majority (86%) of transient burning/stinging events for Eligard

3 month were reported

as mild.

Pain was generally reported as brief in duration and mild in intensity. One of the

reports characterized the erythema as mild and resolved within 7 days. The other was moderate

and resolved within 15 days. Neither patient experienced erythema at multiple injections.

Data Sheet

Version 9.0

All (100%) of transient burning/stinging events for Eligard

4 month were reported as mild.

Pain was generally reported as brief in duration and mild in intensity. Erythema was reported

as mild in all cases and generally resolved within a few days post-injection.

The majority (91%) of transient burning/stinging events for Eligard

6 month were reported

as mild. Pain was generally reported as brief in duration and mild in intensity. Mild bruising

was reported following five (2.3%) study injections and moderate bruising was reported

following two (<1%) study injections.

The following possibly or probably related systemic adverse events occurred during clinical

trials of up to six months of treatment with Eligard

1 month and Eligard

3 month, up to eight

months of treatment with Eligard

4 month and up to 12 months of treatment with Eligard

month, and were reported in

2% of patients (Tables 4 and 5). Often, causality is difficult to

assess in patients with metastatic prostate cancer. Reactions considered not drug- related were

excluded.

More Common Reactions (incidence >2%)

Table 4.

Incidence

(%)

of

Possibly

or

Probably

Related

Systemic

Adverse Events Reported by

2% of Patients Treated with

Eligard

®

1 month and Eligard

®

3 month for up to six months,

Eligard

®

4 month up to eight months and Eligard

®

6 month up

to 12 months

Adverse Event

Eligard

®

1

month

1

N (%)

Eligard

®

3

month

2

N (%)

Eligard

®

4

month

2

N (%)

Eligard

®

6

month

2

N (%)

Body as a

Whole

Malaise and Fatigue

21 (17.5%)

7 (6.0 %)

12 (13.3%)

13 (11.7)

Weakness

4 (3.6%)

Dizziness

4 (3.3%)

4 (4.4 %)

Cardiovascular

Hot flashes/sweats *

68 (56.7%)

66 (56.4%)

66 (73.3%)

64 (57.7)

Genitourinary

Atrophy of Testes *

6 (5.0%)

4 (4.4%)

8 (7.2)

Nocturia

2 (2.2 %)

Urinary frequency

3 (2.6 %)

2 (2.2 %)

Digestive

Gastroenteritis/

Colitis

3 (2.5%)

Nausea

4 (3.4 %)

2 (2.2 %)

Reproductive

Gynaecomastia *

2 (2.2 %)

4 (3.6)

Testicular pain

2 (2.2 %)

Skin

Clamminess *

4 (4.4 %)

Night sweats *

3 (3.3 %)

3 (2.7)

Alopecia

2 (2.2 %)

Pruritis

3 (2.6 %)

Psychiatric

Decreased libido *

3 (3.3 %)

Musculoskeletal

Myalgia

2 (2.2 %)

5 (4.5)

Arthralgia

4 (3.4 %)

Pain in limb

3 (2.7)

adverse events are classified using ICD–9 terms

adverse events are classified using MedDRA terms

* Expected pharmacological consequences of testosterone suppression.

Data Sheet

Version 9.0

Less Common Reactions (incidence <2%)

Table 5.

Possibly

or

Probably

Related

Systemic

Adverse

Events

Reported by < 2% of Patients Treated with Eligard

®

1 month

1

and Eligard

®

3 month

2

for up to six months, Eligard

®

4 month

2

up to eight months and Eligard

®

6 month

2

for up to 12 months

Body System

Adverse Event

General

Sweating, insomnia, syncope, rigors, weakness, lethargy

Gastrointestinal

Flatulence, constipation, dyspepsia

Haematologic

Decreased red blood cell count, haematocrit and haemoglobin

Metabolic

Weight gain

Musculoskeletal

Tremor, backache, joint pain, muscle atrophy, limb pain

Nervous

Disturbance of smell and taste, depression, vertigo

Psychiatric

Insomnia, depression, loss of libido*

Skin

Alopecia, clamminess, night sweats*, sweating increased*

Urogenital / Reproductive

Decreased

libido*,

gynaecomastia,

breast

tenderness*,

testicular

atrophy*,

testicular pain, erectile dysfunction*, penis disorder*, reduced penile size

Renal

Difficulties with urination, pain on urination, scanty urination, bladder spasm,

blood in urine and urinary retention, urinary urgency, incontinence, nocturia

Vascular

Hypertension, hypotension

adverse events are classified using ICD–9 terms

adverse events are classified using MedDRA terms

* Expected pharmacological consequence of testosterone suppression.

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 analogue. It can be anticipated

that long periods of medical castration in men will have effects on bone density.

Antiandrogen therapy significantly increases the risk for fractures owing to osteoporosis. Only

limited data is available on this issue. Fractures owing to osteoporosis were observed in 5% of

patients following 22 months of pharmacological androgen deprivation therapy and in 4% of

patients following 5 to 10 years of treatment. The risk for fractures owing to osteoporosis is

generally higher than the risk for pathological fractures.

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, with a majority occurring within two weeks of the

first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as a

sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and

sometimes cardiovascular collapse. Immediate medical attention has been required.

Data Sheet

Version 9.0

Other Adverse Effects

During

post-market

surveillance

with

LH-RH

agonists;

diabetes mellitus,

myocardial

infarction

cerebrovascular accident and sudden cardiac death have also been reported (see

PRECAUTIONS).

OVERDOSAGE

In clinical trials using daily subcutaneous leuprorelin acetate in patients with prostate cancer,

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.

In case of overdose, immediately contact the Poisons Information Centre for advice (In

Australia, call 13 11 26. In New Zealand, call 0800 764 766)

DOSAGE AND ADMINISTRATION

IMPORTANT:

Allow the product to reach room temperature before using

. Once mixed,

Eligard

®

must be administered within 30 minutes

. Discard the constituted product if not

administered within 30 minutes.

After first opening of the tray or the large outer aluminum pouch, the powder and solvent for

solution for injection are to be immediately reconstituted and administered to the patient.

Although the chemical in-use stability has been demonstrated for 30 minutes at 25°C, the

viscosity of the reconstituted product increases over time. Therefore the product should be

administered to the patient immediately after reconstitution.

The two syringes are coupled and the product is mixed by transferring the contents from

syringe to syringe immediately before administration to the patient. Refer to the full

Mixing

Instructions

at the end of the document for additional instructions.

The syringes are

uncoupled and the needle is attached prior to injection. The product is injected subcutaneously

into areas with adequate amounts of subcutaneous tissue (such as the abdomen) and that do

not have excessive pigment, nodules, lesions, or hair. As with other drugs administered by

subcutaneous injection, the injection site should be varied periodically.

When thoroughly mixed, the suspension will appear a light tan to tan colour (Eligard

month) or a colourless to pale yellow colour (Eligard

3 month, Eligard

4 month and

Eligard

6 month). The mixed solution colour is not representative of product quality. An

occasional slightly grey appearance of the mixed solution may be due to tiny air bubbles and

will not affect the product quality.

Eligard

should not be injected in the arm.

The recommended dose of Eligard

1 month is one injection every month.

The recommended dose of Eligard

3 month is one injection every three months.

The recommended dose of Eligard

4 month is one injection every four months. The

recommended dose of Eligard

6 month is one injection every six months.

Data Sheet

Version 9.0

Eligard

1, 3, 4 and 6 month presentations have different release characteristics and therefore,

fractional, multiple and/or combinational doses are not equivalent to each other

and should

not be given.

Eligard

contains no antimicrobial agent and is for single use in one patient only. Discard

any residue.

The injection delivers leuprorelin acetate, incorporated in a polymer formulation. It is

administered subcutaneously and provides continuous release of leuprorelin for one month

for Eligard

1 month, three months for Eligard

3 month, four months for Eligard

4 month

and six months for Eligard

6 month.

PRESENTATION AND STORAGE CONDITIONS

Eligard

1 month is available in a single use kit that delivers 7.5 mg leuprorelin acetate.

Eligard

3 month is available in a single use kit that delivers 22.5 mg leuprorelin acetate.

Eligard

4 month is available in a single use kit that delivers 30 mg leuprorelin acetate.

Eligard

6 month is available in a single use kit that delivers 45 mg leuprorelin acetate.

Eligard

should be stored below 8°C (refrigerate).

The patient may store Eligard

below 25°C in intact packaging for a period of 8 weeks prior

to administration.

NAME AND ADDRESS

New Zealand Sponsor:

Pharmacy Retailing (NZ) Ltd t/a Healthcare Logistics

P O Box 62027

Sylvia Park

AUCKLAND 1644

MEDICINE CLASSIFICATION

Prescription Medicine

DATE OF PREPARATION

7 March 2016

Eligard

and Atrigel

are registered trademarks of Tolmar Therapeutics, Inc used under

license.

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