Powder and solvent for solution for injection

Powder: white to off-white powder

Solvent: clear, light tan to tan solution

Changed to read

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

4.2     Posology and method of administration

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 3-5 weeks

Changed to read

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.

Administration

Addition of Children and adolescents

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

4.4     Special warnings and special precautions for use

Ommitted:

Pituitary adenomas have been detected in chronic toxicity studies in animals following administration of high doses of leuprorelin acetate in some animal species. This has not been observed in long-term clinical studies with leuprorelin acetate.

Inserted:

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.

4.8     Undesirable effects

hot flushes, reworded as hot flashes

Mild hot flushes occur in approximately 55% of patients. Updated to Mild or moderate hot flashes occur in approximately 58% of patients.

Undesirable effects in clinical studies with Eligard updated

Infections and infestations

Nasopharyngitis added as a common side effect

Nervous system disorders

Hypoaesthesia reclassified as an uncommon side effect (previously listed as common)

Respiratory, thoracic and mediastinal disorders

Dyspnoea added as an uncommon side effect

Gastrointestinal disorders

Diarrhoea removed as a common side effect

Dyspepsia reclassified form common to an uncommon side effect

Vomiting added as an uncommon side effect

Gas pain removed as a rare side effect

Skin and subcutaneous tissue disorders

night sweats reclassified as from an uncommon to a common side effect

Musculoskeletal, connective tissues and bone disorders

Addition of limb pain and myalgia as common side effects.

General Disorders and Administration Site Reaction

Changed from

To

Paragraph updated from

Other adverse events which have been reported in general to occur with leuprorelin acetate treatment include impotence, decrease in libido (both pharmacological consequences of testosterone deprivation), peripheral oedema, pulmonary embolism, palpitations, myalgia, muscle weakness, chills, dyspnoea, peripheral vertigo, rash, amnesia, visual disturbances and skin sensation. Infarction of pre-existing pituitary adenoma 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.

To

Other adverse events which have been reported in general to occur with leuprorelin acetate treatment include peripheral oedema, pulmonary embolism, palpitations, myalgia, 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.

Below paragraph and table removed:

Mild transient burning/stinging following injection is very common. Pain, erythema, bruising and pruritus following injection are common. Induration and ulceration are rare.

4.9     Overdose

Paragraph updated from

There is no clinical experience with the effects of an acute overdose with ELIGARD 7.5 mg. In the event of an overdose the patient should be monitored and supportive treatment given, if considered necessary.

To read

ELIGARD 7.5 mg 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.

5.1       Pharmacodynamic properties

The agonist possesses greater potency than the natural hormone. Updated to read

However, the agonist possesses greater potency than the natural hormone and the time to recovery of testosterone levels may vary between patients.

5.2     Pharmacokinetic properties

Inserted: No drug metabolism study was conducted with ELIGARD.

5.3     Preclinical safety data

Paragraph Updated from

Preclinical studies with leuprorelin acetate, revealed effects on the reproductive system, which were expected from the known pharmacological properties. Leuprorelin acetate did not show teratogenicity. Embryotoxicity/lethality was observed in rabbits.

Carcinogenicity studies

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

Mutagenicity studies

Leuprorelin acetate and ELIGARD 7.5 mg were not mutagenic in a set of in vitro and in vivo assays.

To

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.

6.1     List of excipients

Insertion of 50:50

6.3     Shelf life

Paragraph  updated from

After first opening of one of the trays (tray pack) or the large outer aluminium pouch (pouch pack) the powder and solvent for solution for injection are to be immediately reconstituted and administered to the patient. Chemical and physical in-use stability has been demonstrated for 30 minutes at 25°C. From a microbiological point of view, once reconstituted with sterile vehicle, the product should be administered immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

To

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.

6.4     Special precautions for storage

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

6.5     Nature and contents of container

Updated from

A kit consisting of one large aluminium outer pouch which contains 2 aluminium pouches, a 20-gauge 12.5 mm sterile cannula and a silicone dessicant pouch. One pouch contains one pre-filled polypropylene syringe B and a plunger. The other pouch contains one pre-filled polypropylene syringe A.

To

A kit consisting of one large aluminium outer pouch which contains 2 aluminium pouches, a 20-gauge sterile needle and a silicone desiccant pouch. One pouch contains one pre-filled polypropylene syringe A and a plunger. The other pouch contains one pre-filled polypropylene syringe B.

a sterile 20-gauge 12.5 mm sterile cannula updated to read 20-gauge sterile needle

Inserted:

Not all pack sizes may be marketed

6.6     Instructions for use and handling and disposal

Inserted:

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:

Mixing instruction and diagrams updated for clarification.

9.                  DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Changed from: Date of first authorisation: 26th August 2005 to 13^th October 2005

10.     DATE OF REVISION OF THE TEXT

Updated from December 2006 to May 2009