In section 4.2 the following text has been added:
Infusion of Elaprase at home may be considered for patients who have received several months of treatment in the clinic and who are tolerating their infusions well. Home infusions should be performed under the surveillance of a physician or other healthcare professional.
Section 4.6 reworded as follows:
Elaprase is not indicated for use in women of child bearing potential. No reproductive studies in female animals have been performed.
No effects on male fertility were seen in reproductive studies in male rats.
There are no data from the use of idursulfase in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see Section 5.3). As a precautionary measure, it is preferable to avoid the use of Elaprase during pregnancy.
It is not known whether idursulfase is excreted in human breast milk. Available data in animals have shown excretion of idursulfase in milk (see Section 5.3). A risk to the suckling child cannot be excluded. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Elaprase should be made taking into account the benefit of breast-feeding to the child and the benefit of Elaprase therapy to the woman.
Section 4.7 the following sentence has been deleted:
Excretion of idursulfase in milk has not been studied.
Section 4.8 the table of adverse reactions has been revised in full.
Section 5.1 the following text has been added:
All patients received weekly idursulfase up to 3.2 years in an extension to this study (TKT024EXT).
Among patients who were originally randomised to weekly idursulfase in TKT024, mean maximum improvement in distance walked during six minutes occurred at Month 20 and mean percent predicted FVC peaked at Month 16.
Among all patients, statistically significant mean increases from treatment baseline (TKT024 baseline for TKT024 idursulfase patients and Week 53 baseline for TKT024 placebo patients) were seen in the distance walked 6MWT at the majority of time points tested, with significant mean and percent increases ranging from 13.7m to 41.5m and from 6.4% to 11.7% (maximum at Month 20). At most time points tested, patients who were from the original TKT024 weekly treatment group improved their walking distance to a greater extent that patients in the other 2 treatment groups.
Among all patients, mean % predicted FVC was significantly increased at Month 16, although by Month 36, it was similar to the baseline. Patients with the most severe pulmonary impairment at baseline (as measured by % predicted FVC) tended to show the least improvement.
Statistically significant increases from treatment baseline in absolute FVC volume were seen at most visits for each of the prior TKT024 treatment groups. Mean changes from 0.07L to 0.31L and percent ranged from 6.3% to 25.1% (maximum at Month 30). The mean and percent changes from treatment baseline were greatest in the group of patients from the TKT024 study who had received the weekly dosing, across all time points.
At their final visit 21/31 patients in the TKT024 Weekly group, 24/32 in the TKT024 EOW group and 18/31 patients in the TKT024 placebo group had final normalised urine GAG levels that were below the upper limit of normal. Changes in urinary GAG levels were the earliest signs of clinical improvement with idursulfase treatment and the greatest decreases in urinary GAG were seen within the first 4 months of treatment in all treatment groups; changes from Month 4 to 36 were small. The higher the urinary GAG levels at baseline, the greater the magnitude of decreases in urinary GAG with idursulfase treatment.
The decreases in liver and spleen volumes observed at the end of study TKT024 (week 53) were maintained during the extension study (TKT024EXT) in all patients regardless of the prior treatment they had been assigned. Liver volume normalised by Month 24 for 73% (52 out of 71) of patients with hepatomegaly at baseline. In addition, mean liver volume decreased to a near maximum extent by Month 8 in all patients previously treated, with a slight increase observed at Month 36. The decreases in mean liver volume were seen regardless of age, disease severity, antibody status or neutralising antibody status. Spleen volume normalised by Months 12 and 24 for 9.7% of patients in the TKT024 Weekly group with splenomegaly.
Mean cardiac LVMI remained stable over 36 months of idursulfase treatment within each TKT024 treatment group.
Section 5.3 revised as follows:
Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single dose toxicity, repeated dose toxicity, toxicity to reproduction and development and to male fertility. No reproductive toxicity studies in female animals have been performed.
Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/ foetal development, parturition or postnatal development.
Animal studies have shown excretion of idursulfase in breast milk.
Section 10 - Date amended for the revision of the text.
