ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS

Transcription

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1

2 1. NAME OF THE MEDICINAL PRODUCT Cerezyme 200 U Powder for solution for infusion 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each vial of Cerezyme contains a nominal value of 200 units* of imiglucerase. After reconstitution, each vial of Cerezyme contains 200 units of imiglucerase in 5 ml (40 units per ml). The reconstituted solution must be diluted further. * An enzyme unit (U) is defined as the amount of enzyme that catalyses the hydrolysis of one micromole of the synthetic substrate para-nitrophenyl >-D-glucopyranoside (pnp-glc) per minute at 37 C. For excipients, see PHARMACEUTICAL FORM Powder for solution for infusion, to be reconstituted with water for injections and further diluted in 0.9% sodium chloride intravenous solution. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Cerezyme (imiglucerase) is indicated for use as long-term enzyme replacement therapy in patients with a confirmed diagnosis of Type I Gaucher disease and who exhibit clinically significant manifestations of the disease. Therapy should be directed by physicians knowledgeable in the management of Gaucher disease. Manifestations of Type I Gaucher disease Manifestations of Type I Gaucher disease include one or more of the following conditions: anaemia after exclusion of other causes, such as iron deficiency thrombocytopenia bone disease after exclusion of other causes such as Vitamin D deficiency hepatomegaly or splenomegaly 4.2 Posology and method of administration After reconstitution with water for injections and dilution with 0.9% sodium chloride intravenous solution, the preparation is administered by intravenous infusion over 1 to 2 hours (See section 6.6 "Instructions for use and handling ). Posology for Adults, Children and Elderly Due to the heterogeneity and the multi-systemic nature of Gaucher disease, dosage should be individualised for each patient based on a comprehensive evaluation of the clinical manifestations of the disease. As documented in clinical trials and in post-marketing experience, a range of dosage regimens have proven effective towards some or all of the manifestations of the disease. Initial doses of 60 U/kg of 2

3 body weight once every 2 weeks have shown improvement in haematological and visceral parameters within 6 months of therapy and continued use has either stopped progression of or improved bone disease. Administration of doses as low as 2.5 U/kg of body weight three times a week or 15 U/kg of body weight once every 2 weeks has been shown to improve haematological parameters and organomegaly, but not bone parameters. The usual, and for the patient, most convenient frequency of infusion is once every 2 weeks; this is the frequency of infusion for which the most data are available. Patient responses must be routinely evaluated and dosages should only be adjusted (up or down) based on a comprehensive evaluation of patient response relating to all clinical manifestations of the disease. Once individual patient response for all relevant clinical manifestations is well-established and stabilised, dosages may be adjusted for continued effective therapy, while continuing to closely monitor response parameters and patient well-being. Usual monitoring intervals range from 6 to 12 months. 4.3 Contraindications There are no known contraindications to the use of Cerezyme (imiglucerase), except for hypersensitivity to the active substance or to any of the excipients (See section 4.4 Hypersensitivity ). 4.4 Special warnings and special precautions for use Hypersensitivity Current data suggest that, during the first year of therapy, IgG antibodies to Cerezyme (imiglucerase) are formed in approximately 15% of the treated patients. It appears that patients who will develop IgG antibody are most likely to do so within 6 months of treatment and will rarely develop antibodies to Cerezyme after 12 months of therapy. It is suggested that patients be monitored periodically for IgG antibody formation to imiglucerase. Patients with antibody to Cerezyme (imiglucerase) have a higher risk of hypersensitivity reactions (See section 4.8 Undesirable effects ). If a patient experiences a reaction suggestive of hypersensitivity, subsequent testing for imiglucerase antibodies is advised. In rare cases anaphylactoid reactions have been noted. Further treatment with imiglucerase should be conducted with caution. Most patients have successfully continued therapy after a reduction in the rate of infusion and pretreatment with antihistamines and/or corticosteroids. Patients who have developed antibodies or symptoms of hypersensitivity to Ceredase (alglucerase) should be treated with caution when administering Cerezyme (imiglucerase). Pulmonary hypertension Pulmonary hypertension is a known complication of Gaucher disease. It has been observed both in patients receiving and not receiving enzyme replacement therapy. No causal relationship with enzyme replacement therapy has been established. Patients with respiratory symptoms should be evaluated for the presence of pulmonary hypertension. 4.5 Interaction with other medicinal products and other forms of interaction Interactions between Cerezyme and other medicinal products have not been studied. Other forms of interactions such as with food are unlikely. 4.6 Pregnancy and lactation 3

4 Animal reproductive studies have not been conducted with Cerezyme. It is not known whether Cerezyme can cause foetal harm when administered to a pregnant woman, or can affect reproductive capacity. Cerezyme should be given to a pregnant woman only if clearly needed and after a careful risk/benefit analysis has been conducted for both the mother and the conceptus. It is not known whether this drug is excreted in human milk, therefore caution should be exercised when Cerezyme is administered to a nursing woman. 4.7 Effects on ability to drive and use machines No effects on ability to drive and use machines have been observed. 4.8 Undesirable effects In a small number of patients undesirable effects have been reported which are related to the route of administration: discomfort, pruritus, burning, swelling or sterile abscess at the site of venipuncture. Symptoms suggestive of hypersensitivity have been noted in approximately 3% of the patients. Onset of such symptoms has occurred during or shortly after infusions; these have included pruritus, flushing, urticaria/angioedema, chest discomfort, tachycardia, cyanosis and respiratory symptoms. Hypotension associated with hypersensitivity has also been reported rarely. Patients should be advised to discontinue infusion of the product and contact their physician if these symptoms occur. Additional undesirable adverse effects have been reported in a limited number of patients: nausea, vomiting, abdominal cramping, diarrhoea, rash, fatigue, headache, fever, rigors and dizziness. 4.9 Overdose No case of overdose has been reported. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Enzymes-Imiglucerase (recombinant macrophage targeted >- glucocerebrosidase), ATC code: A16AB02. Imiglucerase (recombinant macrophage targeted >-glucocerebrosidase) catalyses the hydrolysis of the glycolipid, glucocerebroside, to glucose and ceramide following the normal degradation pathway for membrane lipids. Glucocerebroside is primarily derived from haematopoietic cell turnover. Gaucher disease is characterised by a functional deficiency in >-glucocerebrosidase enzymatic activity and the resultant accumulation of lipid glucocerebroside in tissue macrophages, which become engorged and are termed Gaucher cells. Gaucher cells are typically found in liver, spleen and bone marrow and occasionally, as well, in lung, kidney and intestine. Secondary haematologic sequelae include severe anaemia and thrombocytopenia in addition to the characteristic progressive hepatosplenomegaly. The skeletal complications are a common, and frequently the most debilitating and disabling feature of Gaucher disease. Possible skeletal complications are: osteonecrosis, osteopenia with secondary pathological fractures, remodeling failure, osteosclerosis and bone crises. 4

5 5.2 Pharmacokinetic properties During 1 hour intravenous infusions of 4 doses (7.5, 15, 30, 60 U/kg) of Cerezyme (imiglucerase), steady-state enzymatic activity was achieved by 30 minutes. Following infusion, plasma enzymatic activity declined rapidly with a half-life ranging from 3.6 to 10.4 minutes. Plasma clearance ranged from 9.8 to 20.3 ml/min/kg, (mean ± S.D, 14.5 ± 4.0 ml/min/kg). The volume of distribution corrected for weight ranged from 0.09 to 0.15 l/kg (mean ± S.D 0.12 ± 0.02 l/kg). These variables do not appear to be influenced by dose or duration of infusion, however, only 1 or 2 patients were studied at each dose level and infusion rate. 5.3 Preclinical safety data Preclinical data reveal no special hazards to humans based on information on safety pharmacology, single and repeated dose toxicity, and mutagenicity. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients The powder contains the following excipients: mannitol, sodium citrate, citric acid monohydrate, polysorbate Incompatibilities There are no known incompatibilities for Cerezyme. In the absence of incompatibility studies, this medicinal product must not be mixed with other medicinal products. 6.3 Shelf life 2 years. 6.4 Special precautions for storage Store at 2 C - 8 C (refrigerator). If necessary, the product diluted in 0.9% sodium chloride intravenous solution can be stored for up to 24 hours at 2 C and 8 C under protection from light, while avoiding microbial contamination. 6.5 Nature and contents of container Cerezyme is supplied in clear glass 20 ml vials. The closure consists of a siliconised butyl stopper with a tamper proof flip-off cap. Each vial is for single use only. To provide sufficient volume to allow accurate dispensing, each vial is formulated to contain an overfill of 0.3 ml. Package sizes: 1 or 25 vials per carton. 6.6 Instructions for use and handling, and disposal 5

6 The powder for solution for infusion has to be reconstituted with water for injections, diluted with 0.9% sodium chloride intravenous solution and then administered by intravenous infusion. Determine the number of vials to be reconstituted based on the individual patient's dosage regimen and remove the vials from the refrigerator. Occasionally, small dosage adjustments may be made to avoid discarding partially used vials. Dosages may be rounded to the nearest full vial, as long as the monthly administered dosage remains substantially unaltered. Use Aseptic Technique Reconstitution Reconstitute each vial with 5.1 ml water for injections; avoid forceful impact of water for injections on the powder and, by mixing gently, avoid foaming of the solution. The reconstituted volume is 5.3 ml. The ph of the reconstituted solution is approximately 6.1. Before further dilution, visually inspect the reconstituted solution in each vial for foreign particles and discoloration. Do not use vials exhibiting foreign particles or discoloration. After reconstitution, promptly dilute vials and do not store for subsequent use. Cerezyme contains no preservatives. Any unused product or waste material should be disposed of in accordance with local requirements. Dilution The reconstituted solution contains 40 units imiglucerase per ml. The reconstituted volume allows accurate withdrawal of a nominal volume of 5.0 ml (equal to 200 units) from each vial. Withdraw 5.0 ml reconstituted solution from each vial and combine the withdrawn volumes. Then dilute the combined volumes with 0.9% sodium chloride intravenous solution to a total volume of 100 to 200 ml. Mix the infusion solution gently. It is recommended that the diluted solution be administered within 3 hours. The product diluted in 0.9% sodium chloride intravenous solution will retain chemical stability if stored up to 24 hours at 2 C and 8 C under protection from light; but microbiological safety will depend on the reconstitution and dilution having been performed aseptically. Administration Administer by intravenous infusion over 1 to 2 hours. Alternatively, the appropriate dose of Cerezyme may be administered such that a rate not exceeding 1 unit per kg body weight per minute is infused. 7. MARKETING AUTHORISATION HOLDER Genzyme Europe B.V., Gooimeer 10, 1411 DD Naarden, The Netherlands 8. NUMBERS IN THE COMMUNITY REGISTER OF MEDICINAL PRODUCTS EU/1/97/053/001 EU/1/97/053/ DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 6

7 17 November DATE OF REVISION OF THE TEXT 7

8 1. NAME OF THE MEDICINAL PRODUCT Cerezyme 400 U Powder for solution for infusion 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each vial of Cerezyme contains a nominal value of 400 units* of imiglucerase. After reconstitution, each vial of Cerezyme contains 400 units of imiglucerase in 10 ml (40 units per ml). The reconstituted solution must be diluted further. * An enzyme unit (U) is defined as the amount of enzyme that catalyses the hydrolysis of one micromole of the synthetic substrate para-nitrophenyl >-D-glucopyranoside (pnp-glc) per minute at 37 C. For excipients, see PHARMACEUTICAL FORM Powder for solution for infusion, to be reconstituted with water for injections and further diluted in 0.9% sodium chloride intravenous solution. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Cerezyme (imiglucerase) is indicated for use as long-term enzyme replacement therapy in patients with a confirmed diagnosis of Type I Gaucher disease and who exhibit clinically significant manifestations of the disease. Therapy should be directed by physicians knowledgeable in the management of Gaucher disease. Manifestations of Type I Gaucher disease Manifestations of Type I Gaucher disease include one or more of the following conditions: anaemia after exclusion of other causes, such as iron deficiency thrombocytopenia bone disease after exclusion of other causes such as Vitamin D deficiency hepatomegaly or splenomegaly 4.2 Posology and method of administration After reconstitution with water for injections and dilution with 0.9% sodium chloride intravenous solution, the preparation is administered by intravenous infusion over 1 to 2 hours (See section 6.6 "Instructions for use and handling ). Posology for Adults, Children and Elderly Due to the heterogeneity and the multi-systemic nature of Gaucher disease, dosage should be individualised for each patient based on a comprehensive evaluation of the clinical manifestations of the disease. As documented in clinical trials and in post-marketing experience, a range of dosage regimens have proven effective towards some or all of the manifestations of the disease. Initial doses of 60 U/kg of 8

9 body weight once every 2 weeks have shown improvement in haematological and visceral parameters within 6 months of therapy and continued use has either stopped progression of or improved bone disease. Administration of doses as low as 2.5 U/kg of body weight three times a week or 15 U/kg of body weight once every 2 weeks has been shown to improve haematological parameters and organomegaly, but not bone parameters. The usual, and for the patient, most convenient frequency of infusion is once every 2 weeks; this is the frequency of infusion for which the most data are available. Patient responses must be routinely evaluated and dosages should only be adjusted (up or down) based on a comprehensive evaluation of patient response relating to all clinical manifestations of the disease. Once individual patient response for all relevant clinical manifestations is well-established and stabilised, dosages may be adjusted for continued effective therapy, while continuing to closely monitor response parameters and patient well-being. Usual monitoring intervals range from 6 to 12 months. 4.4 Contraindications There are no known contraindications to the use of Cerezyme (imiglucerase), except for hypersensitivity to the active substance or to any of the excipients (See section 4.4 Hypersensitivity ). 4.4 Special warnings and special precautions for use Hypersensitivity Current data suggest that, during the first year of therapy, IgG antibodies to Cerezyme (imiglucerase) are formed in approximately 15% of the treated patients. It appears that patients who will develop IgG antibody are most likely to do so within 6 months of treatment and will rarely develop antibodies to Cerezyme after 12 months of therapy. It is suggested that patients be monitored periodically for IgG antibody formation to imiglucerase. Patients with antibody to Cerezyme (imiglucerase) have a higher risk of hypersensitivity reactions (See section 4.8 Undesirable effects ). If a patient experiences a reaction suggestive of hypersensitivity, subsequent testing for imiglucerase antibodies is advised. In rare cases anaphylactoid reactions have been noted. Further treatment with imiglucerase should be conducted with caution. Most patients have successfully continued therapy after a reduction in the rate of infusion and pretreatment with antihistamines and/or corticosteroids. Patients who have developed antibodies or symptoms of hypersensitivity to Ceredase (alglucerase) should be treated with caution when administering Cerezyme (imiglucerase). Pulmonary hypertension Pulmonary hypertension is a known complication of Gaucher disease. It has been observed both in patients receiving and not receiving enzyme replacement therapy. No causal relationship with enzyme replacement therapy has been established. Patients with respiratory symptoms should be evaluated for the presence of pulmonary hypertension. 4.5 Interaction with other medicinal products and other forms of interaction Interactions between Cerezyme and other medicinal products have not been studied. Other forms of interactions such as with food are unlikely. 4.6 Pregnancy and lactation 9

10 Animal reproductive studies have not been conducted with Cerezyme. It is not known whether Cerezyme can cause foetal harm when administered to a pregnant woman, or can affect reproductive capacity. Cerezyme should be given to a pregnant woman only if clearly needed and after a careful risk/benefit analysis has been conducted for both the mother and the conceptus. It is not known whether this drug is excreted in human milk, therefore caution should be exercised when Cerezyme is administered to a nursing woman. 4.7 Effects on ability to drive and use machines No effects on ability to drive and use machines have been observed. 4.8 Undesirable effects In a small number of patients undesirable effects have been reported which are related to the route of administration: discomfort, pruritus, burning, swelling or sterile abscess at the site of venipuncture. Symptoms suggestive of hypersensitivity have been noted in approximately 3% of the patients. Onset of such symptoms has occurred during or shortly after infusions; these have included pruritus, flushing, urticaria/angioedema, chest discomfort, tachycardia, cyanosis and respiratory symptoms. Hypotension associated with hypersensitivity has also been reported rarely. Patients should be advised to discontinue infusion of the product and contact their physician if these symptoms occur. Additional undesirable adverse effects have been reported in a limited number of patients: nausea, vomiting, abdominal cramping, diarrhoea, rash, fatigue, headache, fever, rigors and dizziness. 4.9 Overdose No case of overdose has been reported. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Enzymes-Imiglucerase (recombinant macrophage targeted >- glucocerebrosidase), ATC code: A16AB02. Imiglucerase (recombinant macrophage targeted >-glucocerebrosidase) catalyses the hydrolysis of the glycolipid, glucocerebroside, to glucose and ceramide following the normal degradation pathway for membrane lipids. Glucocerebroside is primarily derived from haematopoietic cell turnover. Gaucher disease is characterised by a functional deficiency in >-glucocerebrosidase enzymatic activity and the resultant accumulation of lipid glucocerebroside in tissue macrophages, which become engorged and are termed Gaucher cells. Gaucher cells are typically found in liver, spleen and bone marrow and occasionally, as well, in lung, kidney and intestine. Secondary haematologic sequelae include severe anaemia and thrombocytopenia in addition to the characteristic progressive hepatosplenomegaly. The skeletal complications are a common, and frequently the most debilitating and disabling feature of Gaucher disease. Possible skeletal complications are: osteonecrosis, osteopenia with secondary pathological fractures, remodeling failure, osteosclerosis and bone crises. 10

11 5.2 Pharmacokinetic properties During 1 hour intravenous infusions of 4 doses (7.5, 15, 30, 60 U/kg) of Cerezyme (imiglucerase), steady-state enzymatic activity was achieved by 30 minutes. Following infusion, plasma enzymatic activity declined rapidly with a half-life ranging from 3.6 to 10.4 minutes. Plasma clearance ranged from 9.8 to 20.3 ml/min/kg, (mean ± S.D, 14.5 ± 4.0 ml/min/kg). The volume of distribution corrected for weight ranged from 0.09 to 0.15 l/kg (mean ± S.D 0.12 ± 0.02 l/kg). These variables do not appear to be influenced by dose or duration of infusion, however, only 1 or 2 patients were studied at each dose level and infusion rate. 5.3 Preclinical safety data Preclinical data reveal no special hazards to humans based on information on safety pharmacology, single and repeated dose toxicity, and mutagenicity. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients The powder contains the following excipients: mannitol, sodium citrate, citric acid monohydrate, polysorbate Incompatibilities There are no known incompatibilities for Cerezyme. In the absence of incompatibility studies, this medicinal product must not be mixed with other medicinal products. 6.3 Shelf life 2 years. 6.4 Special precautions for storage Store at 2 C - 8 C (refrigerator). If necessary, the product diluted in 0.9% sodium chloride intravenous solution can be stored for up to 24 hours at 2 C and 8 C under protection from light, while avoiding microbial contamination. 6.5 Nature and contents of container Cerezyme is supplied in clear glass 20 ml vials. The closure consists of a siliconised butyl stopper with a tamper proof flip-off cap. Each vial is for single use only. To provide sufficient volume to allow accurate dispensing, each vial is formulated to contain an overfill of 0.6 ml. Package sizes: 1, 5 or 25 vials per carton. 6.6 Instructions for use and handling, and disposal 11

12 The powder for solution for infusion has to be reconstituted with water for injections, diluted with 0.9% sodium chloride intravenous solution and then administered by intravenous infusion. Determine the number of vials to be reconstituted based on the individual patient's dosage regimen and remove the vials from the refrigerator. Occasionally, small dosage adjustments may be made to avoid discarding partially used vials. Dosages may be rounded to the nearest full vial, as long as the monthly administered dosage remains substantially unaltered. Use Aseptic Technique Reconstitution Reconstitute each vial with 10.2 ml water for injections; avoid forceful impact of water for injections on the powder and, by mixing gently, avoid foaming of the solution. The reconstituted volume is 10.6 ml. The ph of the reconstituted solution is approximately 6.1. Before further dilution, visually inspect the reconstituted solution in each vial for foreign particles and discoloration. Do not use vials exhibiting foreign particles or discoloration. After reconstitution, promptly dilute vials and do not store for subsequent use. Cerezyme contains no preservatives. Any unused product or waste material should be disposed of in accordance with local requirements. Dilution The reconstituted solution contains 40 units imiglucerase per ml. The reconstituted volume allows accurate withdrawal of a nominal volume of 10.0 ml (equal to 400 units) from each vial. Withdraw 10.0 ml reconstituted solution from each vial and combine the withdrawn volumes. Then dilute the combined volumes with 0.9% sodium chloride intravenous solution to a total volume of 100 to 200 ml. Mix the infusion solution gently. It is recommended that the diluted solution be administered within 3 hours. The product diluted in 0.9% sodium chloride intravenous solution will retain chemical stability if stored up to 24 hours at 2 C and 8 C under protection from light; but microbiological safety will depend on the reconstitution and dilution having been performed aseptically. Administration Administer by intravenous infusion over 1 to 2 hours. Alternatively, the appropriate dose of Cerezyme may be administered such that a rate not exceeding 1 unit per kg body weight per minute is infused. 7. MARKETING AUTHORISATION HOLDER Genzyme Europe B.V., Gooimeer 10, 1411 DD Naarden, The Netherlands 8. NUMBERS IN THE COMMUNITY REGISTER OF MEDICINAL PRODUCTS EU/1/97/053/003 EU/1/97/053/004 EU/1/97/053/ DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 12

13 17 November DATE OF REVISION OF THE TEXT 13

14 ANNEX III LABELLING AND PACKAGE LEAFLET 14

15 A. LABELLING 15

16 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OR, WHERE THERE IS NO OUTER PACKAGING, ON THE IMMEDIATE PACKAGING 1. NAME OF THE MEDICINAL PRODUCT Cerezyme 200 U Powder for solution for infusion imiglucerase 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each vial of powder contains 200 units of imiglucerase. 3. LIST OF EXCIPIENTS Excipients: Mannitol, Sodium Citrate, Citric acid monohydrate and Polysorbate PHARMACEUTICAL FORM AND CONTENTS 1 vial of powder for solution for infusion. 5. METHOD AND, IF NECESSARY, ROUTE(S) OF ADMINISTRATION For intravenous infusion. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP: {month/year} 9. SPECIAL STORAGE CONDITIONS Store at 2 C - 8 C (in a refrigerator). 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE For single use only. Any unused solution should be discarded. 16

17 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Marketing Authorisation Holder: Genzyme Europe B.V. Gooimeer DD Naarden-NL 12. NUMBER(S) IN THE COMMUNITY REGISTER OF MEDICINAL PRODUCTS EU/1/97/053/ MANUFACTURER S BATCH NUMBER Batch (number): 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE Administration is recommended within 3 hours after reconstitution and dilution for infusion. Read package leaflet prior to use. 17

18 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OR, WHERE THERE IS NO OUTER PACKAGING, ON THE IMMEDIATE PACKAGING 1. NAME OF THE MEDICINAL PRODUCT Cerezyme 200 U Powder for solution for infusion imiglucerase 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each vial of powder contains 200 units of imiglucerase. 3. LIST OF EXCIPIENTS Excipients: Mannitol, Sodium Citrate, Citric acid monohydrate and Polysorbate PHARMACEUTICAL FORM AND CONTENTS 25 vials of powder for solution for infusion. 5. METHOD AND, IF NECESSARY, ROUTE(S) OF ADMINISTRATION For intravenous infusion. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP: {month/year} 9. SPECIAL STORAGE CONDITIONS Store at 2 C - 8 C (in a refrigerator). 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE For single use only. Any unused solution should be discarded. 18

19 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Marketing Authorisation Holder: Genzyme Europe B.V. Gooimeer DD Naarden-NL 12. NUMBER(S) IN THE COMMUNITY REGISTER OF MEDICINAL PRODUCTS EU/1/97/053/ MANUFACTURER S BATCH NUMBER Batch (number): 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE Administration is recommended within 3 hours after reconstitution and dilution for infusion. Read package leaflet prior to use. 19

20 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 1. NAME OF THE MEDICINAL PRODUCT AND IF NECESSARY ROUTE(S) OF ADMINISTRATION Cerezyme 200 U Powder for solution for infusion imiglucerase 2. METHOD OF ADMINISTRATION For intravenous infusion. 3. EXPIRY DATE EXP: {month/year} 4. BATCH NUMBER Batch {number}: 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT Genzyme Europe B.V.-NL Store at 2 C - 8 C (refrigerator). 20

21 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OR, WHERE THERE IS NO OUTER PACKAGING, ON THE IMMEDIATE PACKAGING 1. NAME OF THE MEDICINAL PRODUCT Cerezyme 400 U Powder for solution for infusion imiglucerase 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each vial of powder contains 400 units of imiglucerase. 3. LIST OF EXCIPIENTS Excipients: Mannitol, Sodium Citrate, Citric acid monohydrate and Polysorbate PHARMACEUTICAL FORM AND CONTENTS 1 vial of powder for solution for infusion. 5. METHOD AND, IF NECESSARY, ROUTE(S) OF ADMINISTRATION For intravenous infusion. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP: {month/year} 9. SPECIAL STORAGE CONDITIONS Store at 2 C - 8 C (in a refrigerator). 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE For single use only. Any unused solution should be discarded. 21

22 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Marketing Authorisation Holder: Genzyme Europe B.V. Gooimeer DD Naarden-NL 12. NUMBER(S) IN THE COMMUNITY REGISTER OF MEDICINAL PRODUCTS EU/1/97/053/ MANUFACTURER S BATCH NUMBER Batch (number): 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE Administration is recommended within 3 hours after reconstitution and dilution for infusion. Read package leaflet prior to use. 22

23 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OR, WHERE THERE IS NO OUTER PACKAGING, ON THE IMMEDIATE PACKAGING 1. NAME OF THE MEDICINAL PRODUCT Cerezyme 400 U Powder for solution for infusion imiglucerase 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each vial of powder contains 400 units of imiglucerase. 3. LIST OF EXCIPIENTS Excipients: Mannitol, Sodium Citrate, Citric acid monohydrate and Polysorbate PHARMACEUTICAL FORM AND CONTENTS 5 vials of powder for solution for infusion. 5. METHOD AND, IF NECESSARY, ROUTE(S) OF ADMINISTRATION For intravenous infusion. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP: {month/year} 9. SPECIAL STORAGE CONDITIONS Store at 2 C - 8 C (in a refrigerator). 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE For single use only. Any unused solution should be discarded. 23

24 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Marketing Authorisation Holder: Genzyme Europe B.V. Gooimeer DD Naarden-NL 12. NUMBER(S) IN THE COMMUNITY REGISTER OF MEDICINAL PRODUCTS EU/1/97/053/ MANUFACTURER S BATCH NUMBER Batch (number): 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE Administration is recommended within 3 hours after reconstitution and dilution for infusion. Read package leaflet prior to use. PARTICULARS TO APPEAR ON THE OUTER PACKAGING OR, WHERE THERE IS NO OUTER PACKAGING, ON THE IMMEDIATE PACKAGING 1. NAME OF THE MEDICINAL PRODUCT Cerezyme 400 U Powder for solution for infusion imiglucerase 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each vial of powder contains 400 units of imiglucerase. 3. LIST OF EXCIPIENTS Excipients: Mannitol, Sodium Citrate, Citric acid monohydrate and Polysorbate PHARMACEUTICAL FORM AND CONTENTS 25 vials of powder for solution for infusion. 5. METHOD AND, IF NECESSARY, ROUTE(S) OF ADMINISTRATION For intravenous infusion. 24

25 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP: {month/year} 9. SPECIAL STORAGE CONDITIONS Store at 2 C - 8 C (in a refrigerator). 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE For single use only. Any unused solution should be discarded. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Marketing Authorisation Holder: Genzyme Europe B.V. Gooimeer DD Naarden-NL 12. NUMBER(S) IN THE COMMUNITY REGISTER OF MEDICINAL PRODUCTS EU/1/97/053/ MANUFACTURER S BATCH NUMBER Batch (number): 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE Administration is recommended within 3 hours after reconstitution and dilution for infusion. Read package leaflet prior to use. 25

26 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 1. NAME OF THE MEDICINAL PRODUCT AND IF NECESSARY ROUTE(S) OF ADMINISTRATION Cerezyme 400 U Powder for solution for infusion imiglucerase 2. METHOD OF ADMINISTRATION For intravenous infusion. 3. EXPIRY DATE EXP: {month/year} 4. BATCH NUMBER Batch {number}: 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT Genzyme Europe B.V.-NL Store at 2 C - 8 C (refrigerator). 26

27 B. PACKAGE LEAFLET 27

28 PACKAGE LEAFLET Read all of this leaflet carefully before you start using this medicine. - Keep this leaflet. You may need to read it again. - If you have further questions, please ask your doctor or your pharmacist. - This medicine has been prescribed for you personally and you should not pass it on to others. It may harm them, even if their symptoms are the same as yours. In this leaflet: 1. What Cerezyme is and what it is used for. 2. Before you use Cerezyme. 3. How to use Cerezyme. 4. Possible side effects. 5. Storing Cerezyme. Cerezyme 200 U Powder for solution for infusion Imiglucerase - The active substance is imiglucerase. - The other ingredients are mannitol, sodium citrate, citric acid monohydrate and polysorbate 80. Each vial contains 200 units of imiglucerase. Marketing authorisation holder Genzyme Europe B.V., Gooimeer 10, 1411 DD Naarden, The Netherlands Manufacturing authorisation holder responsible for batch release Genzyme Ltd., 37 Hollands Road, Haverhill, Suffolk CB9 8PU, United Kingdom 1. WHAT CEREZYME IS AND WHAT IT IS USED FOR Cerezyme is supplied as a powder for solution for infusion. The reconstituted solution must be further diluted. Imiglucerase is a modified form of the human enzyme >-glucocerebrosidase produced by recombinant DNA technology. Imiglucerase is used as enzyme replacement therapy when the level of enzyme activity is lower than normal as is observed in Gaucher disease. Cerezyme should be used for patients diagnosed with Type I Gaucher disease, who exhibit clinically significant manifestations of the disease, resulting in one or more of the following signs or symptoms: anaemia (low number of red blood cells), bleeding tendency due to low platelet count, spleen or liver enlargement or bone disease. Therapy should be directed by physicians knowledgeable in the management of Gaucher disease. 2. BEFORE YOU USE CEREZYME Do not use Cerezyme: - if you are hypersensitive (allergic) to imiglucerase or any of the other ingredients of Cerezyme. Take special care with Cerezyme: Hypersensitivity (allergy) 28

29 Some patients may develop IgG antibodies to Cerezyme (imiglucerase). These patients have a higher risk of experiencing hypersensitivity (allergic) reactions to the product. Patients exhibiting unusual reactions should report these to their physician (See also 4. Possible side effects ). In rare cases severe allergic-like reactions have been noted. Treatment in patients who have shown hypersensitivity reactions should be approached with caution. Most patients have successfully resumed therapy after a reduction in the rate of infusion and pretreatment with antihistamines and/or corticosteroids. Pulmonary hypertension Pulmonary hypertension is elevated pressure in the blood vessels of the lungs. The cause may be known (heart-, lung, or liver problems) but in some cases it is unknown. Patients with Gaucher disease may have elevated pressure in the blood vessels of the lungs irrespective of whether they are being treated with Cerezyme or not. So far, no relationship with Cerezyme has been established. In any case, if you have respiratory problems contact your treating physician. Taking Cerezyme with food and drink: Interactions with food are unlikely. Pregnancy Use of Cerezyme during pregnancy is not recommended. Women should consult with their treating physician about the appropriate action to be taken. Breast-feeding Use of Cerezyme during breast-feeding is not recommended. Women should consult with their treating physician about the appropriate action to be taken. Driving and using machines: No effects on ability to drive and use machines have been observed. Important information about some of the ingredients of Cerezyme: Not applicable. Using other medicines: There are no known interactions with other medicinal products. Cerezyme should not be administered as a mixture with other medicinal products in the same infusion. Please inform your doctor or pharmacist if you are taking or have recently taken any other medicines, even those not prescribed. 3. HOW TO USE CEREZYME Instructions for use - reconstitution, dilution and administration The powder for solution for infusion has to be reconstituted with water for injections, diluted in 0.9% sodium chloride intravenous solution and then administered by intravenous infusion. Remove the appropriate number of vials from the refrigerator. The number of vials to be reconstituted is based on the individual patient's dosage regimen. Use Aseptic Technique Reconstitution 29

30 Reconstitute each vial with 5.1 ml water for injections; avoid forceful impact of water for injections on the powder and, by mixing gently, avoid foaming of the solution. The reconstituted volume is 5.3 ml. The ph of the reconstituted solution is approximately 6.1. Before further dilution, visually inspect the reconstituted solution in each vial for foreign particles and discoloration. Do not use vials exhibiting foreign particles or discoloration. After reconstitution, promptly dilute vials and do not store for subsequent use. Cerezyme contains no preservatives. Any unused product or waste material should be disposed of in accordance with local requirements. Dilution The reconstituted solution contains 40 units imiglucerase per ml. The reconstituted volume allows accurate withdrawal of a nominal volume of 5.0 ml (equal to 200 units) from each vial. Withdraw 5.0 ml reconstituted solution from each vial and combine the withdrawn volumes. Then dilute the combined volumes with 0.9% sodium chloride intravenous solution to a total volume of 100 to 200 ml. Mix the infusion solution gently. It is recommended that the diluted solution be administered within 3 hours. The product diluted in 0.9% sodium chloride intravenous solution will retain chemical stability if stored up to 24 hours at 2 C and 8 C under protection from light; but microbiological safety will depend on the reconstitution and dilution having been performed aseptically. Administration Administer by intravenous infusion over 1 to 2 hours. Alternatively, the appropriate dose of Cerezyme may be administered such that a rate not exceeding 1 unit per kg body weight per minute is infused. Dosage The dosage should be individualised for each patient. Disease severity and convenience should be factors considered by your physician when selecting the most appropriate dosage and schedule. Initial doses of 60 U/kg of body weight once every 2 weeks have shown improvement in blood parameters and liver and spleen volumes within 6 months of therapy and continued use has either stopped progression of or improved bone disease. Administration of doses as low as 2.5 U/kg of body weight three times a week or 15 U/kg of body weight once every 2 weeks has been shown to improve blood parameters and liver and spleen volumes, but not bone parameters. The usual and most convenient frequency of infusion is once every 2 weeks; this is the frequency of infusion for which the most data are available. Your physician must routinely evaluate your response to treatment and dosages should only be adjusted (up or down) based on a comprehensive evaluation of your response to all relevant clinical manifestations of the disease. Once a response for all relevant clinical manifestations is well-established and stabilised, your physician may decide to adjust your dosage for continued effective therapy, while continuing to closely monitor response parameters and your well-being. Usual monitoring intervals range from 6 to 12 months. If you have the impression that the effect of Cerezyme is too strong or too weak, talk to your doctor or pharmacist. If you use more Cerezyme than you should: 30

31 There are no cases of overdose of Cerezyme. If you forget to take Cerezyme: Do not take a double dose to make up for forgotten individual doses. Effects when treatment with Cerezyme is stopped: Not applicable. 4. POSSIBLE SIDE EFFECTS Like all medicines, Cerezyme can have side effects. Patients may experience minor adverse events which are associated with the route of administration as with any intravenous infusion, i.e. discomfort, itching, burning, swelling or abscess at the site of venipuncture. Symptoms suggestive of hypersensitivity have been noted in a limited number of patients. Onset of such symptoms has occurred during or shortly after infusions; these have included itching, flushing, urticaria/angioedema, chest discomfort, increased heart rate, bluish skin, and breathlessness. Fall in blood pressure associated with hypersensitivity has also been reported in a very small number of patients. Patients should be advised to discontinue infusion of the product and immediately contact their physician if these symptoms occur. Additional undesirable effects have been reported in a limited number of patients: nausea, vomiting, abdominal cramping, diarrhoea, rash, fatigue, headache, fever, rigors and dizziness. If you notice any side effects not mentioned in this leaflet, please inform your doctor or pharmacist. 5. STORING CEREZYME Keep out of the reach and sight of children. Store at 2 C - 8 C (in a refrigerator). Do not use Cerezyme after the expiry date printed on the labelling after the letters EXP. This leaflet was last approved on 31

32 Further information For any information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder. België/Belgique/Belgien: N.V. Consultancy Guy Derkinderen S.A. Vijfstraten 17 B-3140 Keerbergen Tél/Tel: Danmark: Genzyme Europe B.V. Gooimeer 10 NL-1411 DD Naarden, Holland Tlf: Deutschland: Genzyme GmbH Röntgenstrasse 4 D Alzenau Tel: Fax: Ελλάδα: Jasonpharm Co. Υµηττού 97 GR Αθήνα Τηλ: España: Genzyme, S.L. Damián Sánchez López, 3 E San Sebastián de los Reyes (Madrid) Tel: France: Genzyme S.A. ZI des Beaux Soleils 9, Chaussée Jules César Bâtiment 2 BP 225 Osny F Cergy-Pontoise Cedex Tél: Ireland: Genzyme Therapeutics 4620 Kingsgate Cascade Way Oxford Business Park South Oxford OX4 2SU - UK Tel: Luxembourg/Luxemburg: N.V. Consultancy Guy Derkinderen S.A. Vijfstraten 17 B-3140 Keerbergen, Belgique/Belgien Tél: Nederland: Genzyme Nederland Gooimeer 10 NL-1411 DD Naarden Tel: Österreich: Genzyme GmbH Office Central and Eastern Europe Bleicherstrasse 10 D Konstanz, Deutschland Tel: Portugal: Enzifarma - Diagnóstica e Farmacêutica, Lda. Taguspark - Parque de Ciência e Tecnologia Núcleo Central 184 P Oeiras Tel: Suomi/Finland: Genzyme Europe B.V. Gooimeer 10 NL-1411 DD Naarden, Alankomaat/ Nederländerna Puh./Tlf: Sverige: Genzyme Europe B.V. Gooimeer 10 NL-1411 DD Naarden, Nederländerna Tel: United Kingdom: Genzyme Therapeutics 4620 Kingsgate Cascade Way Oxford Business Park South Oxford OX4 2SU - UK Tel:

33 Italia: Genzyme Srl Via Scaglia Est 144 I Modena Tel:

34 PACKAGE LEAFLET Read all of this leaflet carefully before you start using this medicine. - Keep this leaflet. You may need to read it again. - If you have further questions, please ask your doctor or your pharmacist. - This medicine has been prescribed for you personally and you should not pass it on to others. It may harm them, even if their symptoms are the same as yours. In this leaflet: 1. What Cerezyme is and what it is used for. 2. Before you use Cerezyme. 3. How to use Cerezyme. 4. Possible side effects. 5. Storing Cerezyme. Cerezyme 400 U Powder for solution for infusion imiglucerase - The active substance is imiglucerase. - The other ingredients are mannitol, sodium citrate, citric acid monohydrate and polysorbate 80. Each vial contains 400 units of imiglucerase. Marketing authorisation holder Genzyme Europe B.V., Gooimeer 10, 1411 DD Naarden, The Netherlands Manufacturing authorisation holder responsible for batch release Genzyme Ltd., 37 Hollands Road, Haverhill, Suffolk CB9 8PU, United Kingdom 1. WHAT CEREZYME IS AND WHAT IT IS USED FOR Cerezyme is supplied as a powder for solution for infusion. The reconstituted solution must be further diluted. Imiglucerase is a modified form of the human enzyme >-glucocerebrosidase produced by recombinant DNA technology. Imiglucerase is used as enzyme replacement therapy when the level of enzyme activity is lower than normal as is observed in Gaucher disease. Cerezyme should be used for patients diagnosed with Type I Gaucher disease, who exhibit clinically significant manifestations of the disease, resulting in one or more of the following signs or symptoms: anaemia (low number of red blood cells), bleeding tendency due to low platelet count, spleen or liver enlargement or bone disease. Therapy should be directed by physicians knowledgeable in the management of Gaucher disease. 2. BEFORE YOU USE CEREZYME Do not use Cerezyme: - if you are hypersensitive (allergic) to imiglucerase or any of the other ingredients of Cerezyme. Take special care with Cerezyme: Hypersensitivity (allergy) 34

35 Some patients may develop IgG antibodies to Cerezyme (imiglucerase). These patients have a higher risk of experiencing hypersensitivity (allergic) reactions to the product. Patients exhibiting unusual reactions should report these to their physician (See also 4. Possible side effects ). In rare cases severe allergic-like reactions have been noted. Treatment in patients who have shown hypersensitivity reactions should be approached with caution. Most patients have successfully resumed therapy after a reduction in the rate of infusion and pretreatment with antihistamines and/or corticosteroids. Pulmonary hypertension Pulmonary hypertension is elevated pressure in the blood vessels of the lungs. The cause may be known (heart-, lung, or liver problems) but in some cases it is unknown. Patients with Gaucher disease may have elevated pressure in the blood vessels of the lungs irrespective of whether they are being treated with Cerezyme or not. So far, no relationship with Cerezyme has been established. In any case, if you have respiratory problems contact your treating physician. Taking Cerezyme with food and drink: Interactions with food are unlikely. Pregnancy Use of Cerezyme during pregnancy is not recommended. Women should consult with their treating physician about the appropriate action to be taken. Breast-feeding Use of Cerezyme during breast-feeding is not recommended. Women should consult with their treating physician about the appropriate action to be taken. Driving and using machines: No effects on ability to drive and use machines have been observed. Important information about some of the ingredients of Cerezyme: Not applicable. Using other medicines: There are no known interactions with other medicinal products. Cerezyme should not be administered as a mixture with other medicinal products in the same infusion. Please inform your doctor or pharmacist if you are taking or have recently taken any other medicines, even those not prescribed. 3. HOW TO USE CEREZYME Instructions for use - reconstitution, dilution and administration The powder for solution for infusion has to be reconstituted with water for injections, diluted in 0.9% sodium chloride intravenous solution and then administered by intravenous infusion. Remove the appropriate number of vials from the refrigerator. The number of vials to be reconstituted is based on the individual patient's dosage regimen. Use Aseptic Technique Reconstitution 35

36 Reconstitute each vial with 10.2 ml water for injections; avoid forceful impact of water for injections on the powder and, by mixing gently, avoid foaming of the solution. The reconstituted volume is 10.6 ml. The ph of the reconstituted solution is approximately 6.1. Before further dilution, visually inspect the reconstituted solution in each vial for foreign particles and discoloration. Do not use vials exhibiting foreign particles or discoloration. After reconstitution, promptly dilute vials and do not store for subsequent use. Cerezyme contains no preservatives. Any unused product or waste material should be disposed of in accordance with local requirements. Dilution The reconstituted solution contains 40 units imiglucerase per ml. The reconstituted volume allows accurate withdrawal of a nominal volume of 10.0 ml (equal to 400 units) from each vial. Withdraw 10.0 ml reconstituted solution from each vial and combine the withdrawn volumes. Then dilute the combined volumes with 0.9% sodium chloride intravenous solution to a total volume of 100 to 200 ml. Mix the infusion solution gently. It is recommended that the diluted solution be administered within 3 hours. The product diluted in 0.9% sodium chloride intravenous solution will retain chemical stability if stored up to 24 hours at 2 C and 8 C under protection from light; but microbiological safety will depend on the reconstitution and dilution having been performed aseptically. Administration Administer by intravenous infusion over 1 to 2 hours. Alternatively, the appropriate dose of Cerezyme may be administered such that a rate not exceeding 1 unit per kg body weight per minute is infused. Dosage The dosage should be individualised for each patient. Disease severity and convenience should be factors considered by your physician when selecting the most appropriate dosage and schedule. Initial doses of 60 U/kg of body weight once every 2 weeks have shown improvement in blood parameters and liver and spleen volumes within 6 months of therapy and continued use has either stopped progression of or improved bone disease. Administration of doses as low as 2.5 U/kg of body weight three times a week or 15 U/kg of body weight once every 2 weeks has been shown to improve blood parameters and liver and spleen volumes, but not bone parameters. The usual and most convenient frequency of infusion is once every 2 weeks; this is the frequency of infusion for which the most data are available. Your physician must routinely evaluate your response to treatment and dosages should only be adjusted (up or down) based on a comprehensive evaluation of your response to all relevant clinical manifestations of the disease. Once a response for all relevant clinical manifestations is well-established and stabilised, your physician may decide to adjust your dosage for continued effective therapy, while continuing to closely monitor response parameters and your well-being. Usual monitoring intervals range from 6 to 12 months. If you have the impression that the effect of Cerezyme is too strong or too weak, talk to your doctor or pharmacist. If you use more Cerezyme than you should: 36