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 Adverse Reactions). 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 Adverse Reactions). 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. 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 authorization holder.
Patients who have experienced IARs (and in particular anaphylactic reactions) should be treated with caution when re-administering Myozyme (see Contraindications and Adverse Reactions). 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: In clinical studies, the majority of patients developed IgG antibodies to alglucosidase alfa typically within 3 months of treatment. Thus seroconversion is expected to occur in most patients treated with Myozyme. A tendency was observed for infantile-onset patients treated with a higher dose (40 mg/kg) to develop higher titres of IgG antibodies. There does not appear to be a correlation between the onset of IARs and the time of IgG antibody formation. A limited number of the IgG positive patients evaluated tested positive for inhibitory effects on in vitro testing. Due to the rarity of the condition and the limited experience to date, the effect of IgG antibody formation on safety and efficacy is currently not fully established. The probability of a poor outcome and of developing high and sustained IgG antibody titres 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 IgG antibody titres also occur in some CRIM-positive patients. The cause of a poor clinical outcome and of developing high and sustained IgG antibody titres is thought to be multifactorial. IgG antibody titres should be regularly monitored.
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 Adverse Reactions). 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 Adverse Reactions). Nephrotic syndrome was observed in a few Pompe patients treated with alglucosidase alfa and who had high IgG antibody titres (≥ 102,400) (see Adverse Reactions). 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: 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.
Risk of cardiac arrhythmia and sudden cardiac death during general anaesthesia for central venous catheter placement: Caution should be used when administering general anesthesia for the placement of a central venous catheter or for other surgical procedures in infantile-onset Pompe disease patients with cardiac hypertrophy.
Cardiac arrhythmia, including ventricular fibrillation, ventricular tachycardia and bradycardia, resulting in cardiac arrest or death, or requiring cardiac resuscitation or defibrillation have been associated with the use of general anesthesia in infantile-onset Pompe disease patients with cardiac hypertrophy.
Risk of acute cardiorespiratory failure: Acute cardiorespiratory failure requiring intubation and inotropic support has been observed after infusion with Myozyme in a few infantile-onset Pompe disease patient with underlying cardiac hypertrophy, possibly associated with fluid overload with intravenous administration of Myozyme.
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 has been reported as an infusion associated reaction, this may affect the ability to drive and use machines on the day of the infusion.