FDA label 041b42a5-b825-4802-86f6-9b6425e4f465

WARNING: ANAPHYLAXIS, SEVERE ALLERGIC AND IMMUNE MEDIATED REACTIONS and RISK OF CARDIORESPIRATORY FAILURE Life-threatening anaphylactic, severe allergic and immune mediated reactions have been observed in some patients during MYOZYME ® infusions. Therefore, appropriate medical support should be readily available when MYOZYME is administered. [see Warnings and Precautions (5.1) ] Risk of Cardiorespiratory Failure Patients with compromised cardiac or respiratory function may be at risk for serious acute exacerbation of their cardiac or respiratory compromise due to infusion reactions, and require additional monitoring. [see Warnings and Precautions (5.3) ] WARNING: ANAPHYLAXIS, SEVERE ALLERGIC AND IMMUNE MEDIATED REACTIONS and RISK OF CARDIORESPIRATORY FAILURE Life-threatening anaphylactic, severe allergic and immune mediated reactions have been observed in some patients during MYOZYME ® infusions. Therefore, appropriate medical support should be readily available when MYOZYME is administered. Risk of Cardiorespiratory Failure Patients with compromised cardiac or respiratory function may be at risk of serious acute exacerbation of their cardiac or respiratory compromise due to infusion reactions, and require additional monitoring. See Warnings and Precautions ( 5 )

5 WARNINGS AND PRECAUTIONS Life-threatening anaphylactic, severe allergic and immune mediated reactions: Ensure that appropriate medical support is readily available. If severe allergic or anaphylactic reactions occur, consider immediate discontinuation of MYOZYME and initiate appropriate medical treatment. ( 5.1 ) Severe cutaneous and systemic immune mediated reactions: Monitor patients for the development of systemic immune mediated reactions involving skin and other organs. ( 5.2 ) Acute cardiorespiratory failure: Patients with compromised cardiac or respiratory function may be at risk of acute cardiorespiratory failure. Appropriate medical support and monitoring measures should be readily available. ( 5.3 ) Cardiac arrhythmias and sudden cardiac death during general anesthesia: Caution should be used when administering general anesthesia for the placement of a central venous catheter intended for MYOZYME infusion. ( 5.4 ) 5.1 Anaphylaxis and Allergic Reactions (see Boxed Warning ) Anaphylaxis and severe allergic reactions have been reported in some patients during and up to three hours after MYOZYME infusion, some of which were IgE-mediated. Some of the reactions were life-threatening and included: anaphylactic shock, cardiac arrest, respiratory distress, hypotension, bradycardia, hypoxia, bronchospasm, throat tightness, dyspnea, angioedema, and urticaria. Interventions have included: cardiopulmonary resuscitation, mechanical ventilatory support, oxygen supplementation, intravenous (IV) fluids, hospitalization, treatment with inhaled beta-adrenergic agonists, epinephrine, and IV corticosteroids [see Adverse Reactions (6) ] . In clinical trials and postmarketing safety experience with MYOZYME, approximately 1% of patients developed anaphylactic shock and/or cardiac arrest during MYOZYME infusion that required life-support measures. In clinical trials and expanded access programs with MYOZYME, approximately 14% of patients treated with MYOZYME have developed allergic reactions that involved at least 2 of 3 body systems, cutaneous, respiratory or cardiovascular systems. These events included: Cardiovascular: hypotension, cyanosis, hypertension, tachycardia, ventricular extrasystoles, bradycardia, pallor, flushing, nodal rhythm, peripheral coldness; Respiratory: tachypnea, wheezing/bronchospasm, rales, throat tightness, hypoxia, dyspnea, cough, respiratory tract irritation, decreased oxygen saturation; Cutaneous: angioedema, urticaria, rash, erythema, periorbital edema, pruritus, hyperhidrosis, cold sweat, livedo reticularis [see Adverse Reactions (6) ] . If anaphylactic or other severe allergic reactions occur, immediate discontinuation of the administration of MYOZYME should be considered, and appropriate medical treatment should be initiated. Because of the potential for severe allergic reactions, appropriate medical support measures, including cardiopulmonary resuscitation equipment, should be readily available when MYOZYME is administered. The risks and benefits of re-administering MYOZYME following an anaphylactic or severe allergic reaction should be considered. Some patients have been rechallenged and have continued to receive MYOZYME under close clinical supervision. Extreme care should be exercised, with appropriate resuscitation measures available, if the decision is made to re-administer the product [see Adverse Reactions (6.3) ] . 5.2 Immune Mediated Reactions Severe cutaneous and systemic immune mediated reactions have been reported in postmarketing safety experience with MYOZYME in at least 2 patients, including ulcerative and necrotizing skin lesions, and possible type III immune mediated reactions [see Adverse Reactions (6.3) ] . These reactions occurred several weeks to 3 years after initiation of MYOZYME infusions. Skin biopsy in one patient demonstrated deposition of anti-rh-GAA antibodies in the lesion. Another patient developed severe inflammatory arthropathy in association with fever and elevated erythrocyte sedimentation rate. Nephrotic syndrome secondary to membranous glomerulonephritis was observed in a few Pompe patients treated with alglucosidase alfa and who had persistently positive anti-rhGAA IgG antibody titers [see Adverse Reactions (6.3) ] . In these patients renal biopsy was consistent with immune complex deposition. Patients improved following treatment interruption. It is therefore recommended to perform periodic urinalysis. Patients should be monitored for the development of systemic immune mediated reactions involving skin and other organs while receiving MYOZYME. If immune mediated reactions occur, discontinuation of the administration of MYOZYME 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 successfully been rechallenged and have continued to receive alglucosidase alfa under close clinical supervision. 5.3 Risk of Acute Cardiorespiratory Failure (see Boxed Warning ) Acute cardiorespiratory failure requiring intubation and inotropic support has been observed up to 72 hours after infusion with MYOZYME in infantile-onset Pompe disease patients with underlying cardiac hypertrophy, possibly associated with fluid overload with intravenous administration of MYOZYME [see Instructions for Use (2.2) ] . Patients with acute underlying respiratory illness, compromised cardiac function and/or sepsis may be at risk of serious exacerbation of their cardiac or respiratory compromise during infusions. Appropriate medical support and monitoring measures should be readily available during MYOZYME infusion, and infants with cardiac dysfunction may require prolonged observation times that should be individualized based on the needs of the patient [see Dosage and Administration (2.2) ] . 5.4 Risk of Cardiac Arrhythmia and Sudden Cardiac Death During General Anesthesia for Central Venous Catheter Placement Administration of general anesthesia can be complicated by the presence of severe cardiac and skeletal (including respiratory) muscle weakness. Therefore, caution should be used when administering general anesthesia for the placement of a central venous catheter intended for MYOZYME infusion. Ventricular arrhythmias and bradycardia, resulting in cardiac arrest or death, or requiring cardiac resuscitation or defibrillation have been observed in infantile-onset Pompe disease patients with cardiac hypertrophy during general anesthesia for central venous catheter placement. 5.5 Infusion Reactions Infusion reactions occurred in 20 of 39 (51%) patients treated with MYOZYME in clinical studies [see Adverse Reactions (6) ] . Some reactions were severe. Severe infusion reactions reported in more than 1 patient in clinical studies and the expanded access program included: fever, decreased oxygen saturation, tachycardia, cyanosis and hypotension. Other infusion reactions reported in more than 1 patient in clinical studies and the expanded access program included: rash, flushing, urticaria, fever, cough, tachycardia, decreased oxygen saturation, vomiting, tachypnea, agitation, increased blood pressure/hypertension, cyanosis, 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. Some patients were pre-treated with antihistamines, antipyretics and/or steroids. Infusion reactions occurred in some patients after receiving antipyretics, antihistamines, or steroids. Infusion reactions may occur at any time during, or up to 2 hours after, the infusion of MYOZYME, 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 reactions. Therefore, these patients should be monitored more closely during administration of MYOZYME. Patients with an acute illness at the time of MYOZYME infusion may be at greater risk for infusion reactions. Careful consideration should be given to the patient's clinical status prior to administration of MYOZYME. If an infusion reaction occurs, decreasing the infusion rate, temporarily stopping the infusion, and/or administration of antihistamines and/or antipyretics may ameliorate the symptoms. If severe infusion or allergic reactions occur, immediate discontinuation of the administration of MYOZYME should be considered, and appropriate medical treatment should be initiated [see Adverse Reactions (6.1) ] . Severe infusion reactions are generally managed with infusion interruption, administration of antihistamines, corticosteroids, intravenous fluids, and/or oxygen, when clinically indicated. Patients who have experienced infusion reactions should be treated with caution when they are re-administered MYOZYME. 5.6 Monitoring: Laboratory Tests Patients should be monitored for IgG antibody formation every 3 months for 2 years and then annually thereafter. Testing for IgG titers may also be considered if patients develop allergic or other immune mediated reactions. Patients who experience anaphylactic or allergic reactions may also be tested for IgE antibodies to alglucosidase alfa and other mediators of anaphylaxis . There are no marketed tests for antibodies against alglucosidase alfa. Contact your local Genzyme representative or Genzyme Corporation at 1-800-745-4447 for information on testing and to obtain a sample collection box. Results from 2 intravenous repeated-dose animal toxicology studies using doses of 100 or 200 mg/kg MYOZYME (about 1.6 to 3.2 times the recommended human dose based on body surface area) in Cynomolgus monkeys to evaluate the possibility of liver accumulation over time showed GAA levels above background in liver tissue several days following the last dose; however, no concurrent changes in liver enzymes or histopathology were observed. Liver enzymes should be evaluated prior to the initiation of MYOZYME treatment and periodically thereafter.

5.1 Anaphylaxis and Allergic Reactions (see Boxed Warning ) Anaphylaxis and severe allergic reactions have been reported in some patients during and up to three hours after MYOZYME infusion, some of which were IgE-mediated. Some of the reactions were life-threatening and included: anaphylactic shock, cardiac arrest, respiratory distress, hypotension, bradycardia, hypoxia, bronchospasm, throat tightness, dyspnea, angioedema, and urticaria. Interventions have included: cardiopulmonary resuscitation, mechanical ventilatory support, oxygen supplementation, intravenous (IV) fluids, hospitalization, treatment with inhaled beta-adrenergic agonists, epinephrine, and IV corticosteroids [see Adverse Reactions (6) ] . In clinical trials and postmarketing safety experience with MYOZYME, approximately 1% of patients developed anaphylactic shock and/or cardiac arrest during MYOZYME infusion that required life-support measures. In clinical trials and expanded access programs with MYOZYME, approximately 14% of patients treated with MYOZYME have developed allergic reactions that involved at least 2 of 3 body systems, cutaneous, respiratory or cardiovascular systems. These events included: Cardiovascular: hypotension, cyanosis, hypertension, tachycardia, ventricular extrasystoles, bradycardia, pallor, flushing, nodal rhythm, peripheral coldness; Respiratory: tachypnea, wheezing/bronchospasm, rales, throat tightness, hypoxia, dyspnea, cough, respiratory tract irritation, decreased oxygen saturation; Cutaneous: angioedema, urticaria, rash, erythema, periorbital edema, pruritus, hyperhidrosis, cold sweat, livedo reticularis [see Adverse Reactions (6) ] . If anaphylactic or other severe allergic reactions occur, immediate discontinuation of the administration of MYOZYME should be considered, and appropriate medical treatment should be initiated. Because of the potential for severe allergic reactions, appropriate medical support measures, including cardiopulmonary resuscitation equipment, should be readily available when MYOZYME is administered. The risks and benefits of re-administering MYOZYME following an anaphylactic or severe allergic reaction should be considered. Some patients have been rechallenged and have continued to receive MYOZYME under close clinical supervision. Extreme care should be exercised, with appropriate resuscitation measures available, if the decision is made to re-administer the product [see Adverse Reactions (6.3) ] .

5.2 Immune Mediated Reactions Severe cutaneous and systemic immune mediated reactions have been reported in postmarketing safety experience with MYOZYME in at least 2 patients, including ulcerative and necrotizing skin lesions, and possible type III immune mediated reactions [see Adverse Reactions (6.3) ] . These reactions occurred several weeks to 3 years after initiation of MYOZYME infusions. Skin biopsy in one patient demonstrated deposition of anti-rh-GAA antibodies in the lesion. Another patient developed severe inflammatory arthropathy in association with fever and elevated erythrocyte sedimentation rate. Nephrotic syndrome secondary to membranous glomerulonephritis was observed in a few Pompe patients treated with alglucosidase alfa and who had persistently positive anti-rhGAA IgG antibody titers [see Adverse Reactions (6.3) ] . In these patients renal biopsy was consistent with immune complex deposition. Patients improved following treatment interruption. It is therefore recommended to perform periodic urinalysis. Patients should be monitored for the development of systemic immune mediated reactions involving skin and other organs while receiving MYOZYME. If immune mediated reactions occur, discontinuation of the administration of MYOZYME 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 successfully been rechallenged and have continued to receive alglucosidase alfa under close clinical supervision.

5.3 Risk of Acute Cardiorespiratory Failure (see Boxed Warning ) Acute cardiorespiratory failure requiring intubation and inotropic support has been observed up to 72 hours after infusion with MYOZYME in infantile-onset Pompe disease patients with underlying cardiac hypertrophy, possibly associated with fluid overload with intravenous administration of MYOZYME [see Instructions for Use (2.2) ] . Patients with acute underlying respiratory illness, compromised cardiac function and/or sepsis may be at risk of serious exacerbation of their cardiac or respiratory compromise during infusions. Appropriate medical support and monitoring measures should be readily available during MYOZYME infusion, and infants with cardiac dysfunction may require prolonged observation times that should be individualized based on the needs of the patient [see Dosage and Administration (2.2) ] .

6 ADVERSE REACTIONS 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. ( 6.1 ) The most common reactions requiring intervention were infusion reactions. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genzyme at 1-800-745-4447 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 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 (5.1) ] . 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 (5.3) and Instructions for Use (2.2) ] . 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 (5.5) ] . 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 Preferred Term Number of Patients (N=39) n (%) Number of Adverse Events N Any Adverse Events 39 (100) 1859 General disorders and administration site conditions 38 (97) Pyrexia 36 (92) 169 Respiratory, thoracic and mediastinal disorders 38 (97) Cough 18 (46) 69 Respiratory distress 13 (33) 18 Respiratory failure 12 (31) 24 Rhinorrhea 11 (28) 16 Tachypnea 9 (23) 15 Infections and infestations 37 (95) Pneumonia 18 (46) 43 Otitis media 17 (44) 35 Upper respiratory tract infection 17 (44) 39 Gastroenteritis 16 (41) 17 Pharyngitis 14 (36) 26 Ear infection 13 (33) 23 Oral candidiasis 12 (31) 20 Catheter-related infection 11 (28) 15 Bronchiolitis 9 (23) 10 Nasopharyngitis 9 (23) 25 Gastrointestinal disorders 32 (82) Diarrhea 24 (62) 62 Vomiting 19 (49) 62 Gastroesophageal reflux disease 10 (26) 13 Constipation 9 (23) 14 Skin and subcutaneous tissue disorders 32 (82) Rash 21 (54) 72 Diaper dermatitis 14 (36) 34 Urticaria 8 (21) 25 Investigations 28 (72) Oxygen saturation decreased 16 (41) 44 Cardiac disorders 24 (62) Tachycardia 9 (23) 31 Bradycardia 8 (21) 18 Injury, poisoning and procedural complications 22 (56) Post procedural pain 10 (26) 20 Blood and lymphatic system disorders 17 (44) Anemia 12 (31) 23 Vascular disorders 14 (36) Flushing 8 (21) 15 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%). 6.2 Immunogenicity 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 (12.3) ] . 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 alfa with 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 (5.5) ] . 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 (5.1) ] . Therefore, these patients should be monitored more closely during administration of MYOZYME. 6.3 Postmarketing Experience 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 (5.1) ] . 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 Warning and Precautions (5.3) ] . 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 (5.1) and (5.5) ] . Additional adverse drug reactions included proteinuria and nephrotic syndrome [see Warnings and Precautions (5.2) ] . 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 (5.2) ] .

6.1 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 (5.1) ] . 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 (5.3) and Instructions for Use (2.2) ] . 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 (5.5) ] . 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 Preferred Term Number of Patients (N=39) n (%) Number of Adverse Events N Any Adverse Events 39 (100) 1859 General disorders and administration site conditions 38 (97) Pyrexia 36 (92) 169 Respiratory, thoracic and mediastinal disorders 38 (97) Cough 18 (46) 69 Respiratory distress 13 (33) 18 Respiratory failure 12 (31) 24 Rhinorrhea 11 (28) 16 Tachypnea 9 (23) 15 Infections and infestations 37 (95) Pneumonia 18 (46) 43 Otitis media 17 (44) 35 Upper respiratory tract infection 17 (44) 39 Gastroenteritis 16 (41) 17 Pharyngitis 14 (36) 26 Ear infection 13 (33) 23 Oral candidiasis 12 (31) 20 Catheter-related infection 11 (28) 15 Bronchiolitis 9 (23) 10 Nasopharyngitis 9 (23) 25 Gastrointestinal disorders 32 (82) Diarrhea 24 (62) 62 Vomiting 19 (49) 62 Gastroesophageal reflux disease 10 (26) 13 Constipation 9 (23) 14 Skin and subcutaneous tissue disorders 32 (82) Rash 21 (54) 72 Diaper dermatitis 14 (36) 34 Urticaria 8 (21) 25 Investigations 28 (72) Oxygen saturation decreased 16 (41) 44 Cardiac disorders 24 (62) Tachycardia 9 (23) 31 Bradycardia 8 (21) 18 Injury, poisoning and procedural complications 22 (56) Post procedural pain 10 (26) 20 Blood and lymphatic system disorders 17 (44) Anemia 12 (31) 23 Vascular disorders 14 (36) Flushing 8 (21) 15 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%).

6.2 Immunogenicity 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 (12.3) ] . 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 alfa with 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 (5.5) ] . 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 (5.1) ] . Therefore, these patients should be monitored more closely during administration of MYOZYME.

6.3 Postmarketing Experience 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 (5.1) ] . 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 Warning and Precautions (5.3) ] . 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 (5.1) and (5.5) ] . Additional adverse drug reactions included proteinuria and nephrotic syndrome [see Warnings and Precautions (5.2) ] . 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 (5.2) ] .