ELIGARD 45 mg is indicated for the treatment of hormone dependent advanced prostate cancer and for the treatment of high-risk localized and locally advanced hormone dependent prostate cancer in combination with radiotherapy.

Posology

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.

ELIGARD 45 mg may be used as neoadjuvant or adjuvant therapy in combination with radiotherapy in  high-risk localised  and locally  advanced prostate cancer.

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. As lack of efficacy may result from incorrect preparation, reconstitution, or administration, testosterone levels should be evaluated in cases  of suspected or known handling errors (see section 4.4).

In patients with metastatic castration resistant prostate cancer not surgically  castrated  receiving  a  GnRH agonist, such as leuprorelin, and eligible for treatment with androgen biosynthesis inhibitors or androgen receptor inhibitors, treatment with a GnRH agonist may be continued.

Paediatric population

Safety and efficacy in children aged 0 to 18 years have not been established (see also section  4.3).

Specific Patient Populations

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

ELIGARD 45 mg should be prepared, reconstituted and administered only by healthcare professionals who are familiar with these procedures. See section 6.6: Special precautions for disposal and other handling.  If the product is not prepared appropriately, it should not be  administered.

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

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.

Correct reconstitution: Lack of clinical efficacy may occur due to incorrect reconstitution  of  the  product. See section 4.2 and section 6.6 for the instructions for preparation and administration of the product  and for evaluation  of testosterone levels in  cases of suspected or known handling errors.

Androgen deprivation  therapy may prolong the QT interval:

In patients with a history of or risk factors for QT prolongation and in patients receiving concomitant medicinal products that might prolong the QT interval (see section 4.5) physicians should assess the benefit risk ratio including  the potential for Torsade de pointes prior to initiating  ELIGARD  45  mg.

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 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 clinical practice.

Transient testosterone flare: 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.

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 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.

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 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.

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.

Convulsions: Post marketing reports of convulsions have been observed in patients on leuprorelin acetate with or without a history of predisposing factors. Convulsions are to be managed according to the current clinical practice.

Other events: 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.

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.

Since androgen deprivation treatment may prolong the QT interval, the concomitant use of ELIGARD 45 mg with medicinal products known to prolong the QT interval or medicinal products able to induce Torsade de pointes such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide)  antiarrhythmic medicinal products, methadone, moxifloxacin, antipsychotics, etc. should be carefully evaluated (see section 4.4).

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, malaise and fatigue and transient local irritation at the site of injection.  Mild  or moderate hot flashes occur in approximately 58 % of patients.

Tabulated list  of adverse reactions

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, rash, amnesia, and visual disturbances. Muscular atrophy has been observed with long term use of products in this class. 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.

Convulsions have been reported after GnRH agonist analogue administration  (see section 4.4).

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.

Anaphylactic/anaphylactoid reactions have been reported rarely after GnRH agonist analogue administration.

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.

Reporting of suspected adverse  reactions

Reporting suspected adverse reactions after authorisation of the medicinal product  is  important.  It allows continued monitoring of the benefit/risk balance of the medicinal product.  Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.

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.

In a phase III randomized clinical trial including 970 patients with locally advanced prostate cancer (mainly T2c-T4 with some T1c to T2b patients with pathological regional nodal disease) of whom 483 were assigned to short-term androgen suppression (6 months) in combination  with  radiation  therapy and 487 to long-term therapy (3 years), a  non-inferiority  analysis compared  the short-term  to  long- term concomitant and adjuvant hormonal treatment with GnRH agonist (triptorelin or goserelin). The 5-year overall mortality was 19.0% and 15.2%, in the short-term  and long-term  groups,  respectively. The observed Hazard Ratio of  1.42 with  an upper  one-sided  95.71% CI of 1.79 or two-sided 95.71%  CI of 1.09; 1.85 (p = 0.65 for non inferiority), demonstrate that the combination of radiotherapy plus 6 months  of androgen deprivation therapy provides  inferior survival as  compared with radiotherapy plus 3 years of androgen deprivation therapy. Overall survival at 5 years  of long-term treatment and short- term treatment shows 84.8% survival and 81.0%, respectively. Overall quality of life using QLQ-C30  did not differ significantly between the two groups (P= 0.37). Results  are dominated by the population  of patients with locally  advanced tumours.

Evidence for the indication of high-risk localized prostate cancer is based on published studies of radiotherapy combined with GnRH analogues, including leuprorelin acetate. Clinical data from five published studies were analyzed (EORTC 22863, RTOG 85-31, RTOG 92-02, RTOG 8610, and  D’Amico et al., JAMA, 2004), which all demonstrate a benefit for the combination of GnRH analogue with radiotherapy. Clear differentiation of the respective study populations for the indications locally advanced prostate cancer and high-risk localized prostate cancer was not possible in the published studies.

Clinical data have shown that radiotherapy followed by 3 years of androgen deprivation therapy is preferable to radiotherapy followed by 6 months of androgen deprivation therapy.

The recommended duration of androgen deprivation therapy in medical guidelines for T3-T4 patients receiving  radiotherapy is 2-3 years.

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.

Solvent (syringe A):        Poly(DL-lactic-co-glycolic-acid) (85:15)

                                             N-Methylpyrrolidone

Powder (syringe B):         None

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.

Store in a refrigerator (2°C – 8°C); in the original package in order to protect from moisture. This product must be at room temperature prior to injection. Remove from the refrigerator approximately 30 minutes before use. Once outside the refrigerator this product may be stored in its original packaging at room temperature (below 25°C) for up to four  weeks.

Two pre-filled syringes, one cyclic olefin copolymer syringe containing powder (Syringe B), and one polypropylene syringe 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 Lock 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 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  syringes (1 x Syringe A;  1 x Syringe B)

Not all  pack sizes may be marketed.

Allow the product to come to room temperature by removing from the refrigerator approximately 30 minutes prior to use.

Please prepare the patient for injection first, followed by the preparation of the product, using the instructions below. If the product is not prepared using the proper technique, it should not be administered, as lack of clinical efficacy may occur due to incorrect reconstitution of the product.

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 plug 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 (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 and hold back the white plunger to prevent loss of the product.

·       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 gently turning the needle clockwise with approximately a three-quarter turn until the needle  is  secure (Figure 11).

Do  not  over tighten as  this  may cause cracking  of the needle  hub resulting  in  leakage  of the product

during injection.

Should the needle hub crack, appear to be damaged, or have any leakage, the product should not be used. The damaged needle should not be substituted/replaced and the product should not be injected. The entire product should be disposed of securely

In the event of damage to the needle hub, a new replacement product should be used.

Step 12: Pull off the protective needle cap 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.