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4.8 Undesirable effects
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. 6.5 Nature and contents of container Two pre-filled 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 bromobutyl 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/polypropylene 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 /polypropylene 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)
alteration in the skin sensation, chills, peripheral vertigo, rash, amnesia and visual disturbances.
6.5 Nature and contents of container
Two pre-filled 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 bromobutyl 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/polypropylene 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 /polypropylene 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)
· 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 /polypropylene 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)
· A bundle pack containing kits of 2 x 2 pre-filled polypropylene/cyclic olefin copolymer syringes (1 x Syringe A; 1 x Syringe B)
In section 6.5 Nature and contents of container
The syringe material is being changed from Polypropylene to cyclic olefin copolymer
The syringe tip cap and plunger tips material is being changed from Bromobutyl to chorobutyl.
Change detail
Eligard 22.5mg SPC
December 2006 in comparison to May 2009
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
One pre-filled syringe with powder for solution for injection contains 26.9 mg leuprorelin (as acetate). The deliverable amount after reconstitution is 22.5mg leuprorelin acetate.
For excipients, see section 6.1.
Changed to read
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.
3. PHARMACEUTICAL form 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 very common injection site burning, injection site paraesthesia common fatigue, injection site pain, injection site bruising, rigors, weakness uncommon injection site pruritus, lethargy, pain, pyrexia To very common fatigue, injection site burning, injection site paraesthesia common Malaise, injection site pain, injection site bruising, injection site stinging , rigors, weakness uncommon injection site pruritus, lethargy, pain, pyrexia rare injection site ulceration very rare injection site necrosis 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 following injection is very common. Stinging, pain and bruising are common. Erythema and pruritus are uncommon. Table 2: Incidence of local adverse events by number of injections Burning 21.7 % Stinging 5.7 % Pain 3.5 % Ecchymosis 1.7 % Erythema 0.9 % Pruritus 0.4 % 4.9 Overdose Paragraph updated from There is no clinical experience with the effects of an acute overdose with ELIGARD 22.5 mg. In the event of an overdose the patient should be monitored and supportive treatment given, if considered necessary. To read ELIGARD 22.5 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 75:25 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 13th October 2005 10. DATE OF REVISION OF THE TEXT Updated from December 2006 to May 2009
Powder and solvent for solution for injection
Powder: white to off-white powder
Solvent: clear, light tan to tan solution
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
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.
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
very common
injection site burning, injection site paraesthesia
common
fatigue, injection site pain, injection site bruising, rigors, weakness
uncommon
injection site pruritus, lethargy, pain, pyrexia
To
fatigue, injection site burning, injection site paraesthesia
Malaise, injection site pain, injection site bruising, injection site stinging , rigors, weakness
rare
injection site ulceration
very rare
injection site necrosis
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.
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 following injection is very common. Stinging, pain and bruising are common. Erythema and pruritus are uncommon.
Table 2: Incidence of local adverse events by number of injections
Burning
21.7 %
Stinging
5.7 %
Pain
3.5 %
Ecchymosis
1.7 %
Erythema
0.9 %
Pruritus
0.4 %
4.9 Overdose
There is no clinical experience with the effects of an acute overdose with ELIGARD 22.5 mg. In the event of an overdose the patient should be monitored and supportive treatment given, if considered necessary.
To read
ELIGARD 22.5 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.
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 75:25
6.3 Shelf life
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.
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.
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.
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
Not all pack sizes may be marketed
6.6 Instructions for use and handling and disposal
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 13th October 2005
10. DATE OF REVISION OF THE TEXT
Updated from December 2006 to May 2009
Changes Document
Eligard 7.5mg and 22.5mg SPCs
Version October 2005 v December 2006
Main change is that reference is now made to the new tray packs.
Section 4.8
Table 1: Vascular disorders:
Hot flushes changed to hot flashes
Section 6.3 Shelf life
Added in reference to the new tray pack.
Section 6.5 Nature and contents of container
New text inserted describing the new tray pack which may be 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 polypropylene syringe B, a sterile 20-gauge 12.5 mm sterile cannula and a silicone desiccant pouch.”
Section 6.6 Instructions for use and handling and disposal
Points 1 and 2 now include reference to the tray pack.
Section 10. DATE OF REVISION OF THE TEXT
Updated to December 2006