Genzyme Therapeutics

Section 4.4 Inclusion of paragraph on nephrotic syndrome
Section 4.8: update of Adverse Events

Section 10: Date revised

Changes to sections:

2. Qualitative and Quantitative Composition

Removal of the sentence “Alglucosidase alfa is a recombinant form of”

4.1 Therapeutic indications

Addition of the sentence “Myozyme is indicated in adults and paediatric patients of all ages”.

4.2 Posology and method of administration

Method of Administration section has moved to after the Renal & Hepatic impairment section

Under “Paediatric and elderly population” – “administered to children, adolescents” has been changed to “administered to pediatric patients of all ages”

Under “Renal and hepatic impairment” – “hepatic insufficiency” has been changed to “hepatic impairment”

4.4 Special warnings and precautions for use.

The headers “Hypersensitivity/Anaphylactic reactions”,

 “Infusion Associated Reactions”, “Immuogenicity”.

 “Transient Nephrotic syndrome” and “Immune complex-mediated reactions” have been added.

At the end of the first paragraph under the Header “Infusion Associated Reactions” “reported to Genzyme” had been changed to “reported to the marketing authorisation holder”

4.6 Fertility, pregnancy and lactation

The section Fertility has been added

4.7 Effects on ability to drive and use machines

Addition of last sentence

4.8 Undesirable effects

In the first paragraph the sentence “Most adverse events reported in these 39 patients were due to manifestations of Pompe disease and not related to the administration of Myozyme” has been deleted

Changes made in the section “Table – 1” changes also made in the actual table.  Addition of Superscript 4 at the bottom of the table and removal of the first 2 paragraphs after the table. 

Second paragraph from the end, of this section has been removed.

4.9 Overdose

Re-wording of this sentence

5.1 Pharmacodynamics properties

“Alglucosidase alfa” has been removed from the end of the first paragraph

6.1  List of Excipients

Change to - Sodium dihydrogen phosphate monohydrate and Disodium phosphate heptahydrate

6.3 Shelf Life

Changed to 2 years from 24 months

6.4  Special precautions for storage

For storage conditions of the diluted medicinal product, see section 6.3 – has been added.

6.5 Nature and contents of container

The word Clear has been removed from the bracketed section (Clear Type-1 glass)

6.6 Special precautions for disposal and other handling

First sentence has been reworded

At the end of paragraph 3 the section “As Myozyme does not contain a preservative” has been removed.

Under the Dilution section the paragraph has been reworded

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of latest renewal has been added

10 Date of Revision of the Text

Change of date.

Changes to sections:

2. Qualitative and Quantitative Composition

Addition of the sentence “Alglucosidase alfa is a recombinant form of human acid α-glucosidase and is produced in Chinese hamster ovary cells by recombinant DNA technology.”

4.2 Posology and method of administration

Addition of header “Posology” and deletion of “as an intravenous infusion”

Addition of header and infusion instructions “Method of Administration”  “Myozyme should be administered as an intravenous infusion.”  And addition of paragraph “Patient response to treatment should be routinely evaluated based on a comprehensive evaluation of all clinical manifestations of the disease.”

Addition of header “Paediatric and elderly population”

Addition of header “Renal and hepatic impairment” plus addition of paragraph – “For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6”  Deletion of “Patient response to treatment should be routinely evaluated based on a comprehensive evaluation of all clinical manifestations of the disease”

4.4 Special warnings and precautions for use.

Addition of last paragraph – “Severe cutaneous reactions, possibly immune-mediated, have been reported with alglucosidase alfa, including ulcerative and necrotizing skin lesions (see section 4.8). Patients should be monitored for signs and symptoms of systemic immune complex-mediated reactions involving skin and other organs while receiving alglucosidase alfa. If immune-mediated reactions occur, discontinuation of the administration of alglucosidase alfa should be considered and appropriate medical treatment initiated. The risks and benefits of re-administering alglucosidase alfa following an immune-mediated reaction should be considered. Some patients have been successfully rechallenged and continued to receive alglucosidase alfa under close clinical supervision.”

4.5 Interaction with other medicinal products and other forms of interaction

Re-wording of paragraph.

4.6 Fertility, pregnancy and lactation

Addition of Fertility in the header and change of “Lactation” to “Breast-feeding”

4.8 Undesirable effects

Addition of “conjunctivitis, abdominal pain, arthralgia, apnea and respiratory arrest” to “Post-marketing data: unknown frequency (cannot be estimated from the available data)” Also addition of paragraph below “Severe cutaneous reactions, possibly immune-mediated, have been reported with alglucosidase alfa including ulcerative and necrotizing skin lesions (see section 4.4).

5.1 Pharmacodynamic properties

Deletion of “Alglucosidase alfa is a recombinant form of human acid α-glucosidase and is produced by recombinant DNA technology using Chinese Hamester Ovary (CHO) cell culture”

10 Date of Revision of the Text

Change of date.

Changes made in the following sections:


4.1 Therapeutic indications: Addition of statement in relation to late onset data.
4.3 Contraindications: Addition to indicate that hypersensitivity is life threatening when rechallenge was unsucessful.
4.4 Special warnings and precautions for use: Paragraph 7: Indicates that patients experiencing hypersensitivity may be tested for IgE.  Patients at risk for the occurrence of IARs.
4.6 Pregnancy and lactation:  Addition of: “There are no data from the use of alglucosidase alfa in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3) the potential risk to humans is unknown”.

4.8 Undesirable effects:  addition of information relating to late onset pompe disease and addition of Table 1.
5.1 Pharmacodynamic properties:  Paragraph 10. Addition of section on Late-onset Pompe disease.

5.2 Pharmacokinetic properties:  Data for Late-onset Pompe disease included.
5.3 Preclinical safety data:  Addition of: findings resulting from mouse and rabbit embryofoetal study.
10. Date of revision of text date added

In section 4.4 (Special Warnings and Precautions for use) the following has been added;

·     Infantile onset patients who develop high antibody titres appear to be at higher risk for developing more frequent IARs

·     Patients should be closely monitored and all cases of IARs, delayed reactions and possible immunological reactions should be reported.

·    The probability of a poor outcome and of developing high and sustained antibody titers appears higher among CRIM-negative patients (Cross Reactive Immunologic Material; patients in whom no endogenous GAA protein was detected by Western blot analysis) than among CRIM-positive patients (patients in whom endogenous GAA protein was detected by Western blot analysis). However, high and sustained antibody titers also occur in some CRIM-positive patients. The cause of a poor clinical outcome and of developing high and sustained antibody titers is thought to be multi-factorial.  
   
    In Section 4.8 (undesirable effects) the following has been added;
    

A small number of patients (< 1%) in clinical trials and in the commercial setting developed anaphylactic shock and/or cardiac arrest during Myozyme infusion that required life-support measures. Reactions generally occurred shortly after initiation of the infusion. Patients presented with a constellation of signs and symptoms, primarily respiratory, cardiovascular, edematous and/or cutaneous in nature

   Extensive changes have occurred  In Section 5.1 (pharmacodynamic properties)