ELIGARD 22.5 mg powder and solvent for solution for injection

One prefilled syringe with powder for solution for injection contains 22.5 mg leuprorelin acetate, equivalent to 20.87 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 22.5 mg is indicated for the treatment of hormone dependent advanced prostate cancer

Dosage for Adult Males

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

ELIGARD 22.5 mg is administered as a single subcutaneous injection every three months. The injected solution forms a solid medicinal product delivery depot and provides continuous release of leuprorelin acetate over a three-month period.

As a rule, therapy of advanced prostate cancer with ELIGARD 22.5 mg entails long-term treatment and therapy should not be discontinued when remission or improvement occurs.

Response to ELIGARD 22.5 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 22.5 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 with 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 22.5 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 22.5 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 22.5 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 tumors 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 22.5 mg.

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 was presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention is required.

Hyperglycemia and diabetes: Hyperglycemia and an increased risk of developing diabetes have been reported in men receiving GnRH agonists. Hyperglycemia may represent development of diabetes mellitus or worsening of glycemic control in patients with diabetes. Monitor blood glucose and/or glycosylated hemoglobin (HbA1c) periodically in patients receiving a GnRH agonist and manage with current practice for treatment of hyperglycemia or diabetes.

Cardiovascular diseases: 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 low based on the reported odds ratios, and should be eva luated 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 clinical practice.

No pharmacokinetic drug-drug interaction studies have been performed with ELIGARD 22.5 mg. There have been no reports of any interactions of leuprorelin acetate with other medicinal products.

Not applicable as ELIGARD 22.5 mg is contraindicated in women.

No studies on the effects of ELIGARD 22.5 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 22.5mg are mainly subject to the specific pharmacological action of leuprorelin acetate, namely increases and decreases in certain hormone levels. The most commonly reported adverse reactions are hot flashes, nausea, malaise and fatigue and transient local irritation at the site of injection. Mild hot flashes occur in approximately 58% of patients.

The following adverse events were reported during clinical trials with ELIGARD in patients with advanced prostatic 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, muscle weakness, an alteration in the skin sensation, 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 acetate 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 22.5mg 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 acetate, 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 five weeks after initiation of treatment. Mean testosterone levels at six months are 10.1 (± 0.7) ng/dL, comparable to levels following bilateral orchiectomy. All patients who received the full dose of 22.5 mg leuprorelin in the pivotal clinical study reached castrate levels at 5 weeks; 99 % had reached this by day 28. 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 98% 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 98% reduction in mean PSA for ELIGARD 22.5 mg.

Absorption: In patients with advanced carcinoma of the prostate, mean serum leuprorelin concentrations following the initial injection rise to 127ng/ml at 4.6 hr (Cmax) after injection. After the initial increase following each injection (the plateau phase from 3 - 84 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, 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 two thermoformed trays in a cardboard carton. One tray contains one pre-filled polypropylene syringe A, a large plunger rod and a desiccant pouch. The other tray contains pre-filled cyclic olefin copolymer syringe B, a 20-gauge sterile needle and a silicone 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 both trays (tear off the foil from the corner which can be recognized by a small bubble) and empty the contents onto a clean field (two trays containing Syringe A (Figure 1.1) and Syringe B (Figure 1.2)). Discard the desiccant pouches.

Step 2: Pull out and do not unscrew the blue coloured short plunger rod together with the attached grey stopper from Syringe B and discard (Figure 2). Do not attempt to mix the product with two stoppers in place.

Step 3: Gently screw the Syringe B white plunger rod to the remaining grey stopper in Syringe B (Figure 3).

Step 4: Remove the grey rubber cap from Syringe B and put down the Syringe (Figure 4).

Step 5: Hold Syringe A in a vertical position to ensure no liquid leaks out and unscrew the clear cap from Syringe A (Figure 5).

Step 6: Join the two syringes together by pushing in and twisting Syringe B onto Syringe A until secure (Figure 6a and 6b). Do not over tighten.

Step 7: Flip the connected unit over and continue to hold the syringes vertically with Syringe B on the bottom while injecting the liquid contents of Syringe A into Syringe B containing the powder (leuproreline acetate) (Figure 7).

Step 8: Thoroughly mix the product by gently pushing the contents of both syringes back and forth between syringes (60 times in total, which takes approximately 60 seconds) in a horizontal position to obtain a homogenous, viscous solution (Figure 8). Do not bend the syringe system (please note that this may cause leakage as you may partially unscrew the syringes).

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).

Important: After mixing proceed with the next step immediately as the product gets more viscous over time. Do not refrigerate the mixed product.

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

Step 9: 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 pushing down the Syringe A plunger and slightly withdrawing the Syringe B plunger (Figure 9).

Step 10: Twist off Syringe A while continuing to push down on the Syringe A plunger (Figure 10). Ensure that no product leaks out as the needle will then not secure properly when attached.

Please note: one large or a few small air bubbles may remain in the formulation - this is acceptable. Please do not purge the air bubbles from Syringe B at this stage as product may be lost!

Step 11: Hold Syringe B upright. Open pack of the safety needle by peeling back paper tab and take out safety needle. Secure the safety needle to Syringe B by holding the syringe and twisting the needle clockwise to fully seat the needle (Figure 11). Do not over tighten.

Step 12: Pull off the protective needle cover prior to administration (Figure 12).

Important: Do not operate the safety needle mechanism before administration.

Step 13: Prior to administration, purge any large air bubbles from Syringe B. Administer the product subcutaneously. Please ensure that the full amount of the product in Syringe B is injected.

Step 14: After injection, lock the safety shield using any of the activation methods listed below.

1. Closure on a flat surface

Press the safety shield, lever side down, onto a flat surface (Figure 14.1a and b) to cover the needle and lock the shield.

Verify locked position through audible and tactile “click”. Locked position will completely cover needle tip (figure 14.1b).

2. Closure with your thumb

Placing your thumb on the lever, slide the safety shield toward the needle tip (Figure 14.2a and b) to cover the needle and lock the shield.

Verify locked position through audible and tactile “click”. Locked position will completely cover needle tip (figure 14.2b).

Step 15: Once safety shield is locked, immediately dispose of the needle and syringe in an approved sharps container.

Astellas Pharma Co., Ltd.

5 Waterside,

Citywest Business Campus

Naas Road

Dublin 24

Ireland

PA 1241/003/002 

Date of first authorisation: 13 October 2005

Date of last renewal : 20 December 2009

August 2013