Lucrin(r) Depot 3.75mg, 11.25mg and 30mg Prefilled Dual Chamber Syringe (PDS) Injection

Name of the Medicine Non-proprietary Name

Leuprorelin acetate

Description

Lucrin Depot PDS is a formulation of leuprorelin acetate supplied as sterile lyophilised microspheres which, when mixed with the accompanying diluent, forms a suspension. Lucrin Depot contains either 3.75 mg, 11.25 mg or 30 mg of leuprorelin acetate per single dose. Lucrin Depot also contains carmellose sodium, gelatin (3.75mg only), mannitol, polysorbate 80, water for injection, acetic acid (11.25 mg and 30 mg only), PLGA (3.75 mg only), polylactic acid (11.25 mg and 30mg only).

Pharmacology

Pharmacodynamics

Leuprorelin acetate, a GnRH agonist, acts as a potent inhibitor of gonadotropin secretion when given on a continuous basis and in therapeutic doses. Animal and human studies indicate that following an initial stimulation, chronic administration of leuprorelin acetate results in suppression of ovarian and testicular steroidogenesis. This effect is reversible on discontinuation of therapy. Administration of leuprorelin acetate causes inhibition of the growth of certain hormone dependent tumours (prostatic tumours in Nobel 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 of luteinizing hormone (LH) and follicle stimulating hormone (FSH), leading to a transient increase in levels of the gonadal steroids (testosterone and dihydrotestosterone in males, and oestrone and oestradiol in pre-menopausal females). However, continuous administration of leuprorelin acetate results in decreased levels of LH and FSH and sex steroids. In males, testosterone is reduced to castrate or prepubertal levels. In pre- menopausal females, oestrogens are reduced to post-menopausal levels. These hormonal changes occur within a month of initiating medicine therapy at recommended doses.

Prostatic Cancer

The growth and function of the prostate gland is dependent upon the male hormone, testosterone. Treatment of prostatic carcinoma is aimed at achieving a testosterone blockage (chemical castration). Continuous administration of leuprorelin acetate in males results in a decrease of testosterone to castrate or prepubertal levels. Castrate levels of testosterone in prostatic cancer patients have been demonstrated for periods of up to five years.

Gynaecological Use

Since oestrogen stimulates the growth of both uterine and endometrial tissue, the treatment of uterine fibroids and endometriosis with leuprorelin acetate is based on suppression of oestrogen production.

Lucrin Depot PDS DS

Version 4

14 January 2013 Page 1 of 21

Uterine Fibroids

Leiomyoma uteri (uterine fibroids) is a gynaecological disorder characterised by the presence of benign tumours of myometrial origin, for which oestrogen usually functions as a growth-promoting factor. The effect of oestrogen depletion on the leiomyoma results in shrinkage of the fibroids and in alleviation of the symptoms, including menorrhagia and pelvic pain, pressure and discomfort. Improvement in haemoglobin and haematrocrit has been noted following reduction or elimination of menorrhagia.

Endometriosis

The etiology of endometriosis is unclear, but several theories exist regarding its origin. The most probable cause is retrograde menstruation, but other possible sources included surgical transplantation and direct extension of the endometrium. Medical therapy in endometriosis is based on suppression of oestrogen production. The hypo-oestrogenic state resulting from the administration of Lucrin Depot produced atrophic changes in both uterine and ectopic endometrial tissue. This process included abatement of current endometrial implants, prohibition of new lesions, and possible reduction of adhesions, all of which can result in decreased pain and symptoms. In clinical trials, the majority of women experienced improvement in one or more of the signs and symptoms of endometriosis. Suppression of pituitary gonadotropins usually results in elimination of the menstrual cycle. In conjunction with a 6-month course of therapy, following the last 28-day therapeutic period, the median time to resumption of menses was 52 days (range 7 to 183) in the uterine fibroids clinical studies and 51 days (range 9 to 142) in the endometriosis studies. Since both oestrogen and androgen steroidogenesis are suppressed, the androgenic effects seen with other therapies are avoided.

Central Precocious Puberty (CPP)

Central Precocious Puberty (CPP) is a rare condition defined as the appearance of any signs of secondary sexual development before the age of 8 in females and 9 in males. Central precocious puberty is caused by the premature activation of the hypothalmic-pituitary-gonadol axis in the same pattern as occurs at puberty. In children with central precocious puberty (CPP), stimulated and basal gonadotropins are reduced to prepubertal levels. Testosterone and oestradiol are reduced to prepubertal levels in males and females respectively. Reduction of gonadotropins will allow for normal physical and psychological growth and development. Natural maturation occurs when gonadotropins return to pubertal levels following discontinuation of leuprorelin acetate. The following physiologic effects have been noted with the chronic administration of leuprorelin acetate in this patient population.

Skeletal Growth

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

Organ Growth

. Reproductive organs will return to a prepubertal state.

Menses.

Menses, if present, will cease.

In a study of 22 children with central precocious puberty, doses of leuprorelin acetate for Depot Suspension were given every four weeks and plasma levels were determined according to weight categories as summarised in the following table:

Lucrin Depot PDS DS

Version 4

14 January 2013 Page 2 of 21

Pharmacokinetics

leuprorelin acetate is not active when given orally. Bioavailability of this agent following subcutaneous administration is comparable to that after intramuscular administration.

Absorption

Following the administration of a 7.5mg of leuprorelin acetate for depot suspension injection to adult patients, mean peak leuprorelin plasma concentration was almost 20ng/mL at four hours and then declined to 0.36ng/mL at four weeks. However, intact leuprorelin and an inactive major metabolite could not be distinguished by the assay which was employed in the study. Nondetectable leuprorelin plasma concentrations have been observed during chronic leuprorelin acetate for depot suspension 7.5mg administration, but testosterone levels appear to be maintained at castrate levels. Serum levels of leuprorelin acetate 3.75mg were measured in 11 patients with pre-menopausal breast cancer over 12 weeks. Mean leuprorelin acetate levels were above 0.1ng/mL after four weeks and remained stable after re-injection (at 8 and 12 weeks). There was no tendency for drug accumulation. Following a single administration of leuprorelin acetate depot suspension 3-Month (11.25mg), a rapid increase of leuprorelin acetate concentration was observed. A mean peak leuprorelin plasma concentration of 21.82 (+ 11.24) ng/mL was observed three hours after injection. Leuprorelin acetate reached plateau levels within 7 to 14 days after injection. At week 4, a mean leuprorelin plasma concentration of 0.26 (+ 0.10) ng/mL was noted. It then declined to a mean leuprorelin plasma concentration of 0.17 (+ 0.08) ng/mL at 12 weeks. Following a single injection of the 3 - month formulation of leuprorelin acetate depot suspension - 3 month 11.25mg in female subjects, a mean plasma Leuprorelin concentration of 36.3ng/mL was observed at 4 hours. Leuprorelin appeared to be released at a constant rate following the onset of steady-state levels during the third week after dosing and mean level then declined gradually to near the lower limit of detection by 12 weeks. The mean (+ standard deviation) leuprorelin concentration from 3 to 12 weeks was 0.23+0.09ng/mL. However, intact leuprorelin and an inactive major metabolite could not be distinguished by the assay which was employed in the study. The initial burst, followed by the rapid decline to a steady-state level, was similar to the release pattern seen with the monthly formulation. Leuprorelin acetate is continuously released from the lactic acid polymer for a period of 6 months after injection of Lucrin Depot 30mg PDS Injection. The carrier polymer is absorbed over time in a similar fashion to surgical suture material.

Lucrin Depot PDS DS

Version 4

14 January 2013 Page 3 of 21

After single s.c. injection of Lucrin Depot 30mg PDS Injection serum levels of leuprorelin rise quickly with a subsequent decrease to a plateau within a few days. Within two hours mean maximum serum levels of 100 ng/ml are measured. In the plateau phase detectable serum levels were found until up to > 180 days after the last administration.

Distribution

The mean steady-state volume of distribution of leuprorelin following intravenous bolus administration to healthy male volunteers was 27L. 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 7.6L/h, with a terminal elimination half-life of approximately three hours based on a two compartment model. Animal studies have shown 14C-labelled leuprorelin was metabolised into smaller inactive peptides which may be further catabolised. The major metabolite (M-1) plasma concentrations measured in five prostate cancer patients reached maximum concentration two to six hours after dosing and were approximately 6% of the peak parent medicine concentration. One week after dosing, mean plasma M-1 concentrations were approximately 20% of mean leuprorelin concentrations.

Excretion

Following administration of leuprorelin acetate for depot suspension 3.75mg to three patients, less than 5% of the dose was recovered as parent and M-1 metabolite in the urine over 27 days.

Special Populations

The pharmacokinetics of the medicine in hepatically and renally impaired patients have not been determined.

Contraindications

Lucrin Depot is contraindicated in patients with known hypersensitivity to leuprorelin acetate or similar nonapeptides or to any of the inactive components. Isolated cases of anaphylaxis have been reported. In case hormone-independence of the carcinoma has been demonstrated, treatment with Lucrin Depot 30mg PDS Injection is not indicated. After surgical castration, Lucrin Depot 30mg PDS Injection does not offer further reduction of testosterone levels. Lucrin Depot is contraindicated in women who are or may become pregnant while receiving treatment with this medicine. When administered on day 6 of pregnancy at test dosages of 0.00024, 0.0024 and 0.024mg/kg (1/600 to 1/6 the adult dose, 1/1200 to 1/12 of the human paediatric dose) to rabbits, Lucrin Depot produced a dose related increase in major foetal abnormalities. Similar studies in rats failed to demonstrate an increase in foetal malformations. There was increased foetal mortality and decreased foetal weights with the two higher doses of Lucrin Depot in rabbits and with the highest dose (0.024mg/kg) in rats. The effects on foetal mortality are logical consequences of the alterations in hormonal levels brought about by this medicine. Therefore, a possibility exists that spontaneous abortion may occur if the medicine is administered during pregnancy. Lucrin Depot is also contraindicated in women during breastfeeding. Lucrin Depot should not be administered to patients with undiagnosed vaginal bleeding.

Lucrin Depot PDS DS

Version 4

14 January 2013 Page 5 of 21

Precautions

Prostate Cancer

Isolated cases of worsening of signs and symptoms during the first weeks of treatment have been reported with LH-RH analogues. Worsening of symptoms may contribute to paralysis with or without fatal complications. For patients at risk, the physician may consider initiating therapy with daily leuprorelin acetate injection for the first two weeks to facilitate withdrawal of treatment if that is considered necessary. Patients with metastatic vertebral lesions and/or with urinary tract obstruction should be closely observed during the first few weeks of therapy. Bone mineral density changes can occur during any hypo-oestrogenic state. Bone mineral density loss may be reversible after withdrawal of leuprorelin acetate. Hyperglycaemia and an increased risk of developing diabetes have been reported in men receiving GnRH agonists. Hyperglycaemia may represent development of diabetes mellitus or worsening of glycaemic control in patients with diabetes. Monitor blood glucose and/or glycosylated haemoglobin (HbA1C) periodically in patients receiving GnRH agonists, and manage with current practice for treatment of hyperglycaemia or diabetes. Increased risk of developing myocardial infarction, sudden cardiac death and stroke has been reported in association with use of GnRH agonists in men. The risk appears to be low based on the reported odds ratios, and should be evaluated carefully along with cardiovascular risk factors when determining a treatment for patients with prostate cancer. Patients receiving GnRH agonists should be monitored for symptoms and signs suggestive of development of cardiovascular disease and be managed according to current practice. 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 lA (e.g., quinidine, procainamide) or Class lll (e.g., amiodarone, sotalol) antiarrhythmic medications.

Gynaecological Use

During the early phase of therapy, sex steroids temporarily rise above baseline because of the physiologic effect of the medicine. Therefore, an increase in clinical signs and symptoms may be observed during the initial days of therapy, but these dissipate with continued therapy at adequate doses. However, reports of heavy vaginal bleeding requiring medical or surgical intervention with continued therapy have been reported in the treatment of submucous leiomyoma uteri. Since loss of bone density can be anticipated as part of the natural menopause, it may also be expected to occur during a medically induced hypo-oestrogenic state. Bone loss has been found to be reversible after completion of a six month course of leuprorelin acetate. Repeat courses of leuprorelin acetate or any other GnRH agonist following an initial six month course of therapy should not be considered without assessment of the risk of developing osteoporosis. No data are available for women receiving the treatment for a longer period of time.

Lucrin Depot PDS DS

Version 4

14 January 2013 Page 6 of 21

Central Precocious Puberty

During the early phase of therapy, gonadotropins and sex steroids rise above baseline because of the natural stimulatory effect of the medicine. Therefore, an increase in clinical signs and symptoms may be observed (see Pharmacodynamics). Non-compliance with medicine regimen or inadequate dosing may result in inadequate control of the pubertal process. The consequences of poor control include the return of pubertal signs such as menses, breast development, and testicular growth. The long-term consequences of inadequate control of gonadal steroid secretion are unknown, but may include a further compromise of adult stature.

General 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 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

Effects on Fertility

Clinical and pharmacological studies with leuprorelin acetate and similar analogues have shown full reversibility of fertility suppression when the therapy is discontinued after continuous administration for periods of up to 24 weeks.

Use in Pregnancy

Category C (see Contraindications)

The safe use of leuproprelin acetate in pregnancy has not been established clinically. Before starting treatment with leuproprelin acetate, it is advisable to establish whether the patient is pregnant. leuprorelin is not a contraceptive. If contraception is required, a non-hormonal method of contraception should be used.

Use in Lactation (see Contraindications)

It is not known whether leuproprelin acetate is excreted in human milk; therefore Lucrin Depot should not be used by nursing mothers.

Carcinogenicity

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 medicine was administered subcutaneously at high daily doses (0.6 to 4mg/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 leuproprelin acetate-induced tumours or pituitary abnormalities were observed at a dose as high as 60mg/kg for two years. Patients have been treated with leuproprelin acetate for up to three years with doses as high as 10mg/day and for two years with doses as high as 20mg/day without demonstrable pituitary abnormalities.

Genotoxicity

Genotoxic studies have been performed with leuproprelin acetate using bacterial and mammalian systems. These studies provided no evidence of a genotoxic potential.

Lucrin Depot PDS DS

Version 4

14 January 2013 Page 7 of 21

Interactions with other Medicines

No pharmacokinetic-based medicine-medicine interaction studies have been conducted with leuproprelin acetate depot suspension. However, because leuproprelin acetate is a peptide that is primarily degraded by peptidase and not by cytochrome P-450 enzymes as noted in specific studies, and the medicine is only about 46% bound to plasma proteins, medicine interactions would not be expected to occur. Administration of leuproprelin acetate depot in women results in suppression of the pituitary- gonadal system. Normal function is usually restored within three months after leuproprelin acetate depot treatment is discontinued. Therefore, diagnostic tests of pituitary gonadotropic and gonadal functions conducted during treatment and for up to three months after discontinuation of Leuproprelin acetate depot may be misleading.

Effect on Laboratory Tests

Prostate Cancer Response to leuproprelin acetate should be monitored by measuring serum levels of testosterone, as well as prostate specific antigen and acid phosphatase. 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. Castrate levels were reached within two to four weeks and once achieved were maintained for as long as the patients received their injections on time. Transient increases in acid phosphatase levels sometimes occur early in treatment. However, by the fourth week, the elevated levels can be expected to decrease to values at or near baseline. Central Precocious Puberty Response to leuprorelin acetate should be monitored one to two months after the start of therapy with a GnRH stimulation test and sex steroid levels. Measurement of bone age for advancement should be done every 6 to 12 months. Sex steroids may increase or rise above prepubertal levels if the dose is inadequate (see Precautions). Once a therapeutic dose has been established, gonadotropin and sex steroid levels will decline to prepubertal levels.

Effect on ability to drive and use machinery

T

here are no reported effects on the ability to drive or operate machinery. However, as with all medicines care should be taken until the individual effects of Lucrin Depot are known.

Dosage and Administration

Lucrin Depot must be administered under the supervision of a physician. As with other medicines administered by injection, the injection sites should be varied periodically.

Prostatic Cancer

The recommended dose of Lucrin Depot 3.75 mg one injection given intramuscularly or subcutaneously every month. The recommended dose of Lucrin Depot 3 month 11.25 mg is one injection given intramuscularly or subcutaneously every three months The recommended dose of Lucrin Depot 6 month 30 mg is one injection given intramuscularly or subcutaneously every six months. Generally, the treatment of advanced, hormone-sensitive prostate cancer is continued on a long- term basis. In view of potential clinical signs of progression presenting despite adequate treatment, treatment with Lucrin Depot 30 mg should be monitored for success on a regular basis by means of clinical examinations as well as laboratory evaluations of prostate-specific antigen (PSA), and serum testosterone levels. The application interval should be 168 days to maximum 180 days (24 to 26 weeks) in order to avoid a renewed deterioration of symptoms. As animal experimental findings demonstrated, it is crucial to avoid accidental intra-arterial injection, in view of the potential onset of thrombosis of small vessels distal to the injection site.

Uterine Fibroids, Endometriosis or Breast Cancer

The recommended dose of Lucrin Depot 3.75 mg one injection given intramuscularly or subcutaneously every month. The recommended dose of Lucrin Depot 3 month 11.25mg is one injection given intramuscularly or subcutaneously every three months

Lucrin Depot PDS DS

Version 4

14 January 2013 Page 18 of 21

Use of Lucrin in treatment of benign gynaecological conditions should be limited to six months because of possible osteoporotic effects.

Central Precocious Puberty (3.75mg presentation only)

The dose of Lucrin Depot must be individualised for each child. The dose is based on a mg/kg ratio of medicine to body weight. Younger children require higher doses on a mg/kg ratio. For each dosage, after one to two months of initiating therapy or changing doses, the child must be monitored with a GnRH stimulation test, sex steroids, and Tanner staging to confirm downregulation. Measurements of bone age for advancement should be monitored every 6 to 12 months. The dose should be titrated upward until no progression of the condition is noted either clinically and/or by laboratory parameters. The first dose found to result in adequate downregulation can probably be maintained for the duration of therapy in most children. However, there is insufficient data to guide dosage adjustment as patients move into higher weight categories after beginning therapy at very young ages and low dosages. It is recommended that adequate downregulation be verified in such patients whose weight has increased significantly while on therapy. Discontinuation of Lucrin Depot should be considered before age 11 for females and age 12 for males.

Administration Guidelines - Central Precocious Puberty

Initial Dose

The recommended starting dose of Lucrin Depot is 0.3mg/kg (minimum 7.5mg), administered either intramuscularly or subcutaneously. The starting dose is dictated by the child's weight, as follows:

Note:

When two injections are required to achieve the desired total dosage, they should be administered at the same time, two injections should however be administered at different injection sites.

Maintenance Dose

If

total down-regulation is not achieved, the dose should be titrated upward in increments of 3.75mg every four weeks. This dose will be considered the maintenance dose.

Lucrin Depot Reconstitution

For optimal performance of the prefilled dual-chamber syringe (PDS) read and follow the following instructions:

Lucrin Depot PDS DS

Version 4

14 January 2013 Page 19 of 21

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 (6-8 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. Re-shake the suspension if settling occurs.

NOTE: Aspirated blood would be visible just below the luer lock connection if the blood vessel is accidentally penetrated. If present, blood can be seen through the transparent hub of the needle. Lucrin Depot contains no antimicrobial agent and is for single use in one patient only. Discard any residue.

Stability Once Reconstituted

Although the solution has been shown to be stable for 24 hours following reconstitution, since the product does not contain a preservative, the suspension should be discarded if not used immediately. As with other medicines administered by injection, the injection sites should be varied periodically.

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. For advice on the management of overdose please contact the New Zealand Poisons Information Centre on 0800 764 766.

Presentation and Storage Conditions

Lucrin Depot PDS is available in a single dose pack of a dual chamber syringe containing sterile lyophilised microspheres of leuprorelin acetate in the front chamber and 1mL of diluent in the rear chamber. When the contents of the chambers are mixed, Lucrin Depot 3.75mg PDS is administered as a single intramuscular or subcutaneous injection once a month, Lucrin Depot 11.25mg PDS is administered as a single intramuscular or subcutaneous injection once every three months and Lucrin Depot 30mg PDS is administered as a single intramuscular or subcutaneous injection once every six months. Store below 25degC. Do not freeze. Protect from light.

Lucrin Depot PDS DS

Version 4

14 January 2013 Page 20 of 21

Further Information

Information for Parents of Children Treated with Lucrin Depot for Central Precocious Puberty

Prior to starting therapy with leuprorelin acetate Depot Suspension, the parent or guardian must be aware of the importance of continuous therapy. Adherence to four week medicine administration schedules must be accepted if therapy is to be successful.

• During the first two months of therapy, a female may experienced menses or spotting. If bleeding continues beyond the second month, notify the physician.

• Any irritation at the injection site should be reported to the physician immediately.

• Report any unusual signs or symptoms to the physician.

Name and Address of the Sponsor

AbbVie Limited 6th Floor, 156-158 Victoria Street Wellington, 6011 New Zealand

Medicine Schedule

Prescription Medicine

Date of Preparation

14 January 2013 Version 04

Lucrin Depot PDS DS

Version 4

14 January 2013 Page 21 of 21