Astellas Pharma Co. Ltd

ELIGARD 45 mg, powder and solvent for solution for injection

One prefilled syringe with powder for solution for injection contains 45 mg leuprorelin acetate, equivalent to 41.7 mg leuprorelin.

For a full list of excipients, see section 6.1.

Powder and solvent for solution for injection.

Powder (Syringe B):

Pre-filled syringe with a white to off-white powder.

Solvent (Syringe A):

Pre-filled syringe with a clear, colourless to pale yellow solution.

ELIGARD 45 mg is indicated for the treatment of hormone dependent advanced prostate cancer.

Dosage for Adult Males

ELIGARD 45 mg should be administered under the direction of a healthcare professional having available the appropriate expertise for monitoring the response to treatment.

ELIGARD 45 mg is administered as a single subcutaneous injection every six months. The injected solution forms a solid medicinal product delivery depot and provides continuous release of leuprorelin acetate over a six-month period.

As a rule, therapy of advanced prostate cancer with ELIGARD 45 mg entails long-term treatment and therapy should not be discontinued when remission or improvement occurs.

Response to ELIGARD 45 mg should be monitored by clinical parameters and by measuring prostate specific antigen (PSA) serum levels. Clinical studies have shown that testosterone levels increased during the first 3 days of treatment in the majority of non-orchiectomised patients and then decreased to below medical castration levels within 3 - 4 weeks. Once attained, castrate levels were maintained as long as medicinal product therapy continued (< 1% testosterone breakthroughs). In case the patient's response appears to be sub-optimal, it should be confirmed that serum testosterone levels have reached or are remaining at castrate levels.

Administration

The contents of the two pre-filled sterile syringes must be mixed immediately prior to administration of ELIGARD 45 mg by subcutaneous injection.

Regarding the mixing procedure, see section 6.6.

Based on data from animal experience, intra-arterial or intravenous injection, respectively, has to be strictly avoided.

As with other medicinal products administered by subcutaneous injection, the injection site should be varied periodically.

Children and adolescents

There is no experience in children (under the age of 18 years) (see also section 4.3)

Dose Adjustment in Specific Patient Populations

No clinical studies were performed in patients having either liver or kidney impairment.

Hypersensitivity to leuprorelin acetate, to other GnRH agonists or to any of the excipients.

In patients who previously underwent orchiectomy (as with other GnRH agonists, ELIGARD 45 mg does not result in further decrease of serum testosterone in case of surgical castration).

As sole treatment in prostate cancer patients with spinal cord compression or evidence of spinal metastases (see also section 4.4)

ELIGARD 45 mg is contraindicated in women and paediatric patients.

Leuprorelin acetate, like other GnRH agonists, causes a transient increase in serum concentrations of testosterone, dihydrotestosterone and acid phosphatase during the first week of treatment. Patients may experience worsening of symptoms or onset of new symptoms, including bone pain, neuropathy, haematuria, or ureteral or bladder outlet obstruction (see section 4.8). These symptoms usually subside on continuation of therapy.

Additional administration of an appropriate antiandrogen should be considered beginning 3 days prior to leuprorelin 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.

Following surgical castration, ELIGARD 45 mg does not lead to a further decrease in serum testosterone levels in male patients.

Cases of ureteral obstruction and spinal cord compression, which may contribute to paralysis with or without fatal complications, have been reported with GnRH agonists. If spinal cord compression or renal impairment develops, standard treatment of these complications should be instituted.

Patients with vertebral and/or brain metastases as well as patients with urinary tract obstruction should be closely monitored during the first few weeks of therapy.

A proportion of patients will have tumours which are not sensitive to hormone manipulation. Absence of clinical improvement despite adequate testosterone suppression is diagnostic of this condition, which will not benefit from further therapy with ELIGARD.

Decreased bone density has been reported in the medical literature in men who have had orchiectomy or who have been treated with GnRH agonists (see section 4.8).

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. Apart from long lasting testosterone deficiency, increased age, smoking and consumption of alcoholic beverages, obesity and insufficient exercise may have an influence on the development of osteoporosis.

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 GnRH-agonists, with a majority occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention is required.

Precautions

Changes in glucose tolerance have been reported in some patients receiving GnRH agonist therapy. It is advised that diabetic patients are monitored more frequently during treatment with ELIGARD 45 mg.

No pharmacokinetic drug-drug interaction studies have been performed with ELIGARD 45 mg. There have been no reports of any interactions of leuprorelin acetate with other medicinal products.

Not applicable as ELIGARD 45 mg is contraindicated in women.

No studies on the effects of ELIGARD 45 mg on the ability to drive and use machines have been performed.

The ability to drive and operate machines may be impaired due to fatigue, dizziness and visual disturbances being possible side effects of treatment or resulting from the underlying disease.

Adverse reactions seen with ELIGARD are mainly subject to the specific pharmacological action of leuprorelin, namely increases and decreases in certain hormone levels. The most commonly reported adverse reactions are hot flashes, nausea and fatigue and transient local irritation at the site of injection. Mild or moderate hot flashes occur in approximately 58 % of patients.

The following adverse events were reported during clinical trials with ELIGARD in patients with advanced prostate carcinoma. Adverse events are classified, by frequency, as very common (1/10), common (1/100, <1/10), uncommon (1/1,000, <1/100), rare (1/10,000, <1/1,000) and very rare (<1/10,000), not known (cannot be estimated from the available data).

Other adverse events which have been reported in general to occur with leuprorelin acetate treatment include peripheral oedema, pulmonary embolism, palpitations, myalgia, an alteration in the skin sensation, muscle weakness, chills, peripheral vertigo, rash, amnesia, and visual disturbances. Infarction of pre-existing pituitary apoplexy has been reported rarely after administration of both short and long acting GnRH agonists. There have been rare reports of thrombocytopenia and leucopenia. Changes in glucose tolerance have been reported.

Local adverse events reported after injection of ELIGARD are similar to the local adverse events associated with similar subcutaneously injected products.

Generally, these localised adverse events following subcutaneous injection are mild and described as being of brief duration.

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 GnRH analogues. It can be anticipated that long periods of treatment with leuprorelin may show increasing signs of osteoporosis. Regarding the increased risk for fractures owing to osteoporosis (see section 4.4).

Exacerbation of signs and symptoms of the disease

Treatment with leuprorelin can cause exacerbations of signs and symptoms of the disease during the first few weeks. If conditions such as vertebral metastases and/or urinary obstruction or haematuria are aggravated, neurological problems, such as weakness and/or paraesthesia of the lower limbs or worsening of urinary symptoms may occur.

ELIGARD 45mg does not have the potential for abuse, and deliberate overdose is unlikely. There are no reports of abuse or overdose having occurred in clinical practice with leuprorelin, but in the event that excessive exposure becomes a reality, observation and symptomatic supportive treatment are recommended.

Pharmacotherapeutic group: Gonadotropin releasing hormone analogues

ATC code: L02A E02

Leuprorelin acetate is a synthetic nonapeptide agonist of naturally occurring gonadotropin releasing hormone (GnRH) that, when given continuously, inhibits pituitary gonadotropin secretion and suppresses testicular steroidogenesis in males. This effect is reversible upon discontinuation of medicinal product therapy. However, the agonist possesses greater potency than the natural hormone and the time to recovery of testosterone levels may vary between patients.

Administration of leuprorelin acetate results in an initial increase in circulating levels of luteinising hormone (LH) and follicle stimulating hormone (FSH), leading to a transient increase in levels of the gonadal steroids, testosterone and dihydrotestosterone in males. 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 three to four weeks after initiation of treatment. Mean testosterone levels at six months are 10.4 (± 0.53) ng/dL, comparable to levels following bilateral orchiectomy. All but one patient who received the full dose of 45 mg leuprorelin in the pivotal clinical study reached castrate levels at 4 weeks In the vast majority of patients the testosterone levels seen were below 20 ng/dL although the full benefit of these low levels has not yet been established. PSA levels decreased by 97% over six months.

Long-term studies have shown that continuation of therapy maintains testosterone below the castrate level for up to seven years, and presumably indefinitely.

Tumour size was not measured directly during the clinical trial programme, but there was an indirect beneficial tumour response as shown by a 97% reduction in mean PSA for ELIGARD 45 mg.

Absorption: In patients with advanced carcinoma of the prostate, mean serum leuprorelin concentrations following the initial injection rise to 82 ng/ml at 4.4 hr (Cmax) after injection. After the initial increase following each injection (the plateau phase from 3 - 168 days after each dose), serum concentrations remained relatively constant (0.2 - 2 ng/ml). There is no evidence of accumulation during repeated dosing.

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

Elimination: In healthy male volunteers, a 1 mg bolus of leuprorelin acetate administered intravenously revealed that the mean systemic clearance was 8.34 l/h, with a terminal elimination half-life of approximately 3 hours based on a two compartment model.

No excretion studies have been conducted with ELIGARD.

No drug metabolism study was conducted with ELIGARD

Preclinical studies with leuprorelin acetate, revealed in both sexes effects on the reproductive system, which were expected from the known pharmacological properties. These effects were shown to be reversible after discontinuation of the treatment and an appropriate period of regeneration. Leuprorelin acetate did not show teratogenicity. Embryotoxicity/lethality was observed in rabbits, in line with the pharmacological effects of leuprorelin acetate on the reproductive system.

Carcinogenicity studies were performed in rats and mice over 24 months. In rats, a dose-related increase in pituitary apoplexy was observed after subcutaneous administration at doses of 0.6 to 4 mg/kg/day. No such effect was observed in mice.

Leuprorelin acetate and related one-month product ELIGARD 7.5 mg were not mutagenic in a set of in vitro and in vivo assays.

The leuprorelin present in syringe B must only be mixed with the solvent in syringe A and must not be mixed with other medicinal products.

2 years

After first opening of the tray or the large outer aluminium pouch, the powder and solvent for solution for injection are to be immediately reconstituted and administered to the patient.

Once reconstituted: use immediately, as the viscosity of the solution increases with time.

Store in a refrigerator (2°C - 8°C); in the original package in order to protect from moisture.

Two pre-filled cyclic olefin copolymer / polypropylene syringes, one containing powder (Syringe B), and one containing solvent (Syringe A). Together the two syringes comprise a mixing system.

Syringe A has a plunger tip of thermoplastic rubber and is capped with a polyethylene or polypropylene Luer-Lok cover. The syringe tip cap and the two plunger tips of Syringe B are composed of chlorobutyl rubber.

The following pack sizes are available:

• A kit consisting of one large aluminium outer pouch which contains 2 aluminium pouches, a 18-gauge sterile needle and a desiccant pouch. One pouch contains one pre-filled polypropylene syringe A and a large plunger rod for syringe B. The other pouch contains one pre-filled cyclic olefin copolymer syringe B.

• A kit consisting of two thermoformed trays in a cardboard carton. One tray contains pre-filled polypropylene syringe A, a large plunger rod for syringe B and a desiccant pouch. The other tray contains pre-filled cyclic olefin copolymer syringe B, a sterile 18-gauge needle and a desiccant pouch.

• A bundle pack containing kits of 2 x 2 pre-filled polypropylene/cyclic olefin copolymer syringes (1 x Syringe A; 1 x Syringe B)

Not all pack sizes may be marketed.

Allow the product to come to room temperature.

Please prepare the patient for injection first, followed by the preparation of the product, using the instructions below.

Step 1: Open the outer pouch or tray (tear off the foil from the corner which can be recognized by a small bubble) and empty the contents onto a clean field (two pouches or trays containing Syringe A (Figure 1.1) and Syringe B (Figure 1.2)). Discard the desiccant packs.

Please note: The pictures of the syringes and the needle do not reflect the actual sizes.

Step 2: Remove the blue coloured short plunger rod (do not unscrew) and the stopper from Syringe B and discard.(Figure 2.1) Gently screw the spare longer white plunger rod to the remaining grey stopper in syringe B. (Figure 2.2)

Step 3: Hold syringe A in a vertical position to ensure no liquid leaks out and unscrew the clear cap from Syringe A (Figure 3.1). Remove the grey rubber cap from Syringe B (Figure 3.2). Join the two syringes together by pushing in and twisting until secure (Figure 3.3). Do not over tighten. The needle cartridge will not secure properly, if any of the liquid has leaked out.

Step 4: Inject the liquid contents of Syringe A into Syringe B containing the leuprolide acetate. Thoroughly mix the product by gently pushing the contents of both syringes back and forth between syringes (approximately 60 times in total) in a horizontal position to obtain a uniform solution (Figure 4). Do not bend the syringe system. When thoroughly mixed, the viscous solution will appear with a colour in the range of colourless to white to pale yellow (which could include shades of white to pale yellow).

Please note: Product must be mixed as described; shaking WILL NOT provide adequate mixing of the product.

Step 5:Hold the syringes vertically with Syringe B on the bottom. The syringes should remain securely coupled. Draw the entire mixed product into Syringe B (short, wide syringe) by depressing the Syringe A plunger and slightly withdrawing the Syringe B plunger. Uncouple Syringe A while continuing to push down on the Syringe A plunger. (Figure 5). Ensure that no product leaks out as the needle will then not secure properly when attached. Please note: Small air bubbles will remain in the formulation - this is acceptable.

Step 6: Hold Syringe B upright. Remove the cap of the sterile needle cartridge by twisting it (Figure 6.1). Attach the needle cartridge to the end of Syringe B (Figure 6.2) by gently pushing in and turning the needle until it is firmly seated. Do not overtighten. Pull off the needle cartridge cover prior to administration.

Step 7: Once reconstituted: use immediately, as the viscosity of the solution increases with time. For single use only. Any unused solution should be discarded.

Astellas Pharma Co. Ltd.,

25 The courtyard,

Kilcarbery Business Park,

Clondalkin,

Dublin 22,

Ireland

PA 1241/3/3

The date of first authorisation: 26th October 2007

Date of last renewal: 20th December 2009

November 2011