Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The data described below reflect exposure of 39 Pompe disease patients to 20 or 40 mg/kg of MYOZYME administered every other week in 2 separate clinical trials for periods ranging from 1 to 106 weeks (mean 61 weeks). Patients were ages 1 month to 3.5 years at first treatment. The population was nearly evenly distributed in gender (18 females and 21 males).
The most serious adverse reactions reported with MYOZYME were anaphylactic reactions, acute cardiorespiratory failure, and cardiac arrest.
Anaphylactic reactions have been reported during and within 3 hours after MYOZYME infusion [see BOXED WARNING and WARNINGS AND PRECAUTIONS].
Acute cardiorespiratory failure has been observed in a few infantile-onset Pompe disease patients with underlying cardiac hypertrophy, possibly associated with fluid overload with intravenous administration of alglucosidase alfa [see BOXED WARNING and WARNINGS AND PRECAUTIONS and Instructions for Use].
The most common serious treatment-emergent adverse reactions occurring in > 10% of patients observed in clinical studies with MYOZYME were pneumonia, respiratory failure, respiratory distress, catheter-related infection, respiratory syncytial virus infection, gastroenteritis and fever.
The most common adverse reactions requiring intervention in clinical trials were infusion reactions [see WARNINGS AND PRECAUTIONS]. Twenty of 39 patients (51%) treated with MYOZYME in clinical studies developed infusion reactions. Infusion reactions, defined as an adverse reaction occurring during the infusion or within 2 hours after completion of the infusion, that occurred in more than 1 patient in clinical studies and the expanded access program include rash, flushing, urticaria, fever, cough, tachycardia, decreased oxygen saturations, vomiting, tachypnea, agitation, increased blood pressure, cyanosis, hypertension, irritability, pallor, pruritus, retching, rigors, tremor, hypotension, bronchospasm, erythema, face edema, feeling hot, headache, hyperhidrosis, increased lacrimation, livedo reticularis, nausea, periorbital edema, restlessness, and wheezing.
The most common treatment-emergent adverse reactions occurring in ≥ 20% of patients were fever, diarrhea, rash, vomiting, cough, pneumonia, otitis media, upper respiratory tract infection, gastroenteritis and decreased oxygen saturation.
Table 2 enumerates treatment-emergent adverse reactions that occurred in at least 20% of patients treated with MYOZYME in clinical trials described above. Reported frequencies of adverse events have been classified by MedDRA terms.
Table 2: Summary of Adverse Reactions by System Organ Class and Preferred Term Occurring in at Least 20% of Patients Treated with MYOZYME® in Clinical Trials
|System Organ Class
|Number of Patients
|Number of Adverse Events
|Any Adverse Events||39 (100)||1859|
|General disorders and administration site conditions||38 (97)|
|Respiratory, thoracic and mediastinal disorders||38 (97)|
|Respiratory distress||13 (33)||18|
|Respiratory failure||12 (31)||24|
|Infections and infestations||37 (95)|
|Otitis media||17 (44)||35|
|Upper respiratory tract infection||17 (44)||39|
|Ear infection||13 (33)||23|
|Oral candidiasis||12 (31)||20|
|Catheter-related infection||11 (28)||15|
|Gastrointestinal disorders||32 (82)|
|Gastroesophageal reflux disease||10 (26)||13|
|Skin and subcutaneous tissue disorders||32 (82)|
|Diaper dermatitis||14 (36)||34|
|Oxygen saturation decreased||16 (41)||44|
|Cardiac disorders||24 (62)|
|Injury, poisoning and procedural complications||22 (56)|
|Post procedural pain||10 (26)||20|
|Blood and lymphatic system disorders||17 (44)|
|Vascular disorders||14 (36)|
Five additional juvenile-onset Pompe disease patients were evaluated in a single-center, open-label, non-randomized, uncontrolled clinical trial. Patients were ages 5 to 15 years, ambulatory (able to walk at least 10 meters in 6 minutes), and not receiving invasive ventilatory support at study entry. All 5 patients received treatment with 20 mg/kg MYOZYME for 26 weeks. The most common treatment-emergent adverse reactions observed with MYOZYME treatment in this study were headache (4.1%), pharyngitis (9.1%), upper abdominal pain (15.2%), malaise (6.1%) and rhinitis (6.1%).
As with all therapeutic proteins, there is potential for immunogenicity. The majority of patients (34 of 38; 89%) in the two clinical trials tested positive for IgG antibodies to alglucosidase alfa. The data reflect the percentage of patients whose test results were considered positive for antibodies to alglucosidase alfa using an enzyme-linked immunosorbent assay (ELISA) and radioimmunoprecipitation (RIP) assay for alglucosidase alfa-specific IgG antibodies. Most patients who develop antibodies do so within the first 3 months of exposure. There is evidence to suggest that patients developing sustained titers ≥ 12,800 of anti-alglucosidase alfa antibodies may have a poorer clinical response to treatment, or may lose motor function as antibody titers increase. Treated patients who experience a decrease in motor function should be tested for neutralization of enzyme uptake or activity. Five patients with antibody titers ≥ 12,800 at Week 12 had an average increase in clearance of 50% from Week 1 to Week 12 [see CLINICAL PHARMACOLOGY].
Some patients who developed IgG antibodies to alglucosidase alfa in clinical studies or in the postmarketing setting were evaluated for the presence of inhibitory antibodies and tested positive for inhibition of enzyme activity and/or uptake in in vitro assays.
The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to alglucosidase alfawith the incidence of antibodies to other products may be misleading.
The effect of antibody development on the long-term efficacy of MYOZYME is not fully understood. However, CRIM-negative infants have shown poorer clinical response in the presence of high sustained IgG antibody titers and positive inhibitory antibodies.
Infusion reactions were reported in 20 of 39 patients (51%) treated with MYOZYME in clinical studies and appear to be more common in antibody-positive patients: 8 of 15 patients with high antibody titers experienced infusion reactions, whereas none of 3 antibody-negative patients experienced infusion reactions [see WARNINGS AND PRECAUTIONS].
Patients who develop IgE antibodies to alglucosidase alfa appear to be at a higher risk for the occurrence of anaphylaxis and severe allergic reactions [see WARNINGS AND PRECAUTIONS]. Therefore, these patients should be monitored more closely during administration of MYOZYME.
The following adverse reactions have been identified during post-approval use of MYOZYME. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
In postmarketing experience with MYOZYME, severe and serious infusion reactions have been reported, some of which were life-threatening, including anaphylactic shock [see BOXED WARNING and WARNINGS AND PRECAUTIONS]. Acute cardiorespiratory failure, possibly associated with fluid overload, has been reported in infantile-onset Pompe disease patients with pre-existing hypertrophic cardiomyopathy [see BOXED WARNING and WARNINGS AND PRECAUTIONS]. In addition to the infusion reactions reported in clinical trials and expanded access programs, the following infusion reactions have been reported in patients during postmarketing use of MYOZYME: cardiac arrest, respiratory arrest, apnea, stridor, pharyngeal edema, peripheral edema, chest pain, chest discomfort, muscle spasm, fatigue and conjunctivitis [see WARNINGS AND PRECAUTIONS].
Additional adverse drug reactions included proteinuria and nephrotic syndrome [see WARNINGS AND PRECAUTIONS].
Recurrent reactions consisting of flu-like illness or a combination of events such as fever, chills, myalgia, arthralgia, pain, or fatigue occurring after completion of infusions and lasting for 1-3 days have been observed in some patients treated with alglucosidase alfa. The majority of patients were successfully rechallenged with alglucosidase alfa using lower doses and/or pretreatment with anti-inflammatory drugs and/or corticosteroids and were able to continue treatment under close clinical supervision.
Systemic and cutaneous immune mediated reactions, including ulcerative and necrotizing skin lesions, and nephrotic syndrome secondary to membranous glomerulonephritis have been reported in postmarketing safety experience with alglucosidase alfa [see WARNINGS AND PRECAUTIONS].