Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

Traceability
In order to improve the traceability of biological medicinal products, the name of the administered product should be clearly recorded. It is recommended to record the batch number as well.

Hypersensitivity/Anaphylactic reactions
Serious and life-threatening anaphylactic reactions, including anaphylactic shock, have been reported in infantile- and late-onset patients during Myozyme infusions (see section 4.8). Because of the potential for severe infusion associated reactions, appropriate medical support measures, including cardiopulmonary resuscitation equipment, should be readily available when Myozyme is administered.
If severe hypersensitivity or anaphylactic reactions occur, immediate discontinuation of Myozyme infusion should be considered and appropriate medical treatment should be initiated. The current medical standards for emergency treatment of anaphylactic reactions are to be observed.

Infusion Associated Reactions
Approximately half of the patients treated with Myozyme in infantile-onset clinical studies and 28% of the patients treated with Myozyme in a late-onset clinical study developed infusion associated reactions (IARs). IARs are defined as any related adverse event occurring during the infusion or during the hours following infusion. Some reactions were severe (see section 4.8). A tendency was observed in infantile patients treated with a higher dose (40 mg/kg) to experience more symptoms when developing IARs. Infantile onset patients who develop high IgG antibody titres appear to be at higher risk for developing more frequent IARs. However, IARs occurred regardless of antibody titres. Patients with an acute illness (e.g. pneumonia, sepsis) at the time of Myozyme infusion appear to be at greater risk for IARs. Careful consideration should be given to the patient’s clinical status prior to administration of Myozyme. Patients should be closely monitored and all cases of IARs, delayed reactions and possible immunological reactions should be reported to the marketing authorisation holder.

Patients who have experienced IARs (and in particular anaphylactic reactions) should be treated with caution when re-administering Myozyme (see sections 4.3 and 4.8). Mild and transient effects may not require medical treatment or discontinuation of the infusion. Reduction of the infusion rate, temporary interruption of the infusion, or pre-treatment, generally with oral antihistamine and/or antipyretics and/or corticosteroids, has effectively managed most reactions. IARs may occur at any time during the infusion of Myozyme or generally up to 2 hours after, and are more likely with higher infusion rates.


Patients with advanced Pompe disease may have compromised cardiac and respiratory function, which may predispose them to a higher risk of severe complications from infusion associated reactions. Therefore, these patients should be monitored more closely during administration of Myozyme.

Immunogenicity
The effect of IgG antibody formation on safety and efficacy has been evaluated in clinical trials and post-marketing experience. In clinical studies, the majority of patients developed IgG antibodies to alglucosidase alfa and seroconversion typically occured within 3 months of treatment. Thus, development of IgG antibodies is expected to occur in most patients treated with Myozyme. Overall, a correlation was not observed between the onset of IARs and the time of IgG antibody formation. IARs can occur across all levels of antibody titres, however a trend was observed for more frequent IARs with higher titres of IgG antibody. The clinical impact on efficacy is multifactorial, however the development of high and sustained IgG antibody titres is a contributing factor.
With regard to IOPD, a tendency was observed for patients treated with a higher dose (40 mg/kg) to develop higher titres of IgG antibodies. Furthermore, Cross Reactive Immunologic Material (CRIM) status has been shown to be associated with immunogenicity and patients’ responses to enzyme replacement therapies. Negative CRIM status, indicating no endogenous enzyme is detected, is a risk factor to develop high and sustained IgG antibody titres. This risk is higher among CRIM negative patients versus CRIM-positive patients and is a contributing factor to a poor outcome. However, high and sustained IgG antibody titres has also occurred in a limited number of CRIM-positive patients, generally with very low endogenous enzyme.

With respect to LOPD patients, the majority showed either stabilizing or decreasing antibody titres over time. The development of high and sustained IgG antibody titres is infrequent in LOPD patients. Thus, the impact of IgG antibodies is more limited for LOPD patients.

IgG antibody titres should be monitored based on clinical phenotype. Baseline serum sample collection prior to the first infusion is strongly encouraged. For IOPD patients, regular monitoring during first year of treatment (example: every 3 months) is suggested and subsequent monitoring depending on clinical outcomes and antibody titres level. For LOPD patients, antibody development should be assessed within 6 months and subsequent monitoring as clinically warranted based on safety and efficacy considerations.

Patients who experience hypersensitivity reactions may also be tested for IgE antibodies to alglucosidase alfa and other mediators of anaphylaxis. Patients who develop IgE antibodies to alglucosidase alfa appear to be at a higher risk for the occurrence of IARs when Myozyme is re- administered (see section 4.8). Therefore, these patients should be monitored more closely during administration of Myozyme. Some IgE positive patients were successfully rechallenged with Myozyme using a slower infusion rate at lower initial doses and have continued to receive Myozyme under close clinical supervision.

Immune-mediated reactions
Severe cutaneous reactions, possibly immune-mediated, have been reported with alglucosidase alfa, including ulcerative and necrotizing skin lesions (see section 4.8). Nephrotic syndrome was observed in a few patients with Pompe disease treated with alglucosidase alfa and who had high IgG antibody titres (≥ 102,400) (see section 4.8). In these patients renal biopsy showed immune complex deposition. Patients improved following treatment interruption. It is therefore recommended to perform periodic urinalysis among patients with high IgG antibody titres.

Patients should be monitored for signs and symptoms of systemic immune-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.

Immunomodulation
Immunogenicity data from clinical trials and published literature in CRIM-negative infantile-onset patients (IOPD) suggests that the administration of immune tolerance induction (ITI) regimen given to alglucosidase alfa naive patients (prophylactic ITI) may be effective in preventing or reducing the development of High Sustained Antibody Titre (HSAT) against alglucosidase alfa. Data from a small number of patients with HSAT, with or without inhibitory activity, showed limited ITI treatment effect.
Better treatment responses were observed in younger patients with less advanced disease who received prophylactic ITI before development of HSAT, which suggests that early initiation of ITI can result in improved clinical outcomes. ITI regimens may need to be tailored to individual patient needs (see section 5.1).

Patients with Pompe disease are at increased risk of respiratory infections due to the progressive effects of the disease on the respiratory muscles. Patients with Pompe disease treated with immunosuppressive agents may be at further increased risk of developing severe infections and vigilance is recommended. Fatal and life-threatening respiratory infections have been observed in some of these patients.

Effects on Driving

4.7   Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. Because dizziness, somnolence, tremor and hypotension have been reported as an infusion associated reaction, this may affect the ability to drive and use machines on the day of the infusion.