Myozyme 50 mg, powder for concentrate for solution for infusion.

4.9     Overdose

 

There is no experience with overdose of alglucosidase alfa. In clinical studies doses up to 40 mg/kg body weight were used.

 

7.       MARKETING AUTHORISATION HOLDER

 

Genzyme Europe B.V., Paasheuvelweg 25, 1105 BP Amsterdam, The Netherlands

 Section 4.8:

Correction to the HPRA fax number.

Update of section 4.8 of the SmPC to add the adverse reactions infusion site swelling, infusion site induration and infusion site extravasation with a frequency not known. The Package leaflet is updated accordingly

In section 4.8: The HPRA adverse event reporting address has been updated. The Maltese adverse event reporting address has been included.

Section 4.1: deletion of the sentence: “In patients with late-onset Pompe disease, the evidence of efficacy is limited (see section 5.1)”;

Section 4.4: inclusion of Immunomodulation warning as below;

Immunomodulation

Patients with Pompe disease are at risk of respiratory infections due to the progressive effects of the disease on the respiratory muscles. Immunosuppressive agents have been administered in experimental settings in a small number of patients, in an attempt to reduce or prevent the development of antibodies to alglucosidase alfa. Fatal and life-threatening respiratory infections have been observed in some of these patients. Therefore, treating patients with Pompe disease with immunosuppressive agents may further increase the risk of developing severe respiratory infections and vigilance is recommended.

Section 4.8: Inclusion of reporting of adverse reactions advisory. Additionally, the following has been added;

Recurrent reactions consisting of flu-like illness or a combination of events such as fever, chills, myalgia, arthralgia, pain, or fatigue occurring post-infusion and lasting usually for a few days, have been observed in some patients treated with alglucosidase alfa. The majority of patients were successfully re-challenged with alglucosidase alfa using lower doses and/or pretreatment with anti-inflammatory drugs and/or corticosteroids and have continued to receive treatment under close clinical supervision.

Section 5.1: Inclusion of clinical trial information as below:

Late-onset Pompe disease; other clinical trials and analyses

Three independent, open-label, single arm, investigator-initiated studies with Myozyme were conducted:

•             One study in Italy enrolled 74 late-onset patients with up to 48 months follow up.

•             One study in Germany enrolled 38 late-onset patients with 36 months follow up.

•             One study in the Netherlands enrolled 69 late-onset patients with a median follow-up of 23 months.

These three studies with Myozyme (with a follow up of at least 3 years in two studies and a median of 23 months in the other study) suggested stabilisation or improvement of motor function and stabilisation of pulmonary function.

In the above described study in 69 late-onset patients in the Netherlands, Myozyme showed an improvement in muscle strength. However, muscle function only improved in wheelchair independent patients and in those with less pronounced muscle weakness.

In two additional open-label clinical trials with Myozyme with a follow-up of 24 months, ten patients with severe late-onset Pompe disease (moderate to severe motor impairment and assisted ventilation) showed a variable response on measures of motor and respiratory functions, mostly in the form of a modest improvement (AGLU03105, AGLU04107).

In addition: several minor changes were also made to the SPC to bring it in line with the current QRD template.

Shelf life extended from 2 years to 3 years

Section 4.4 Inclusion of paragraph on necrotic syndrome

Section 4.8: update of AEs

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.

None provided