Included as part of the "PRECAUTIONS" Section
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].
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].
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 readministering 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 readminister the product [see ADVERSE 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]. These reactions occurred several weeks to 3 years after initiation of MYOZYME infusions. Skin biopsy in one patient demonstrated deposition of anti-rhGAA 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]. 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 readministering 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. Immune tolerance induction administered in conjunction with MYOZYME may also aid tolerability of alglucosidase alfa under the management of a clinical specialist knowledgeable in immune tolerance induction in pediatric Pompe disease.
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 DOSAGE AND ADMINISTRATION]. 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].
Risk Of Cardiac Arrhythmia And Sudden Cardiac Death During Generalanesthesia 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.
Risk Of Antibody Development
Patients with infantile onset Pompe disease should have a cross-reactive immunologic material (CRIM) assessment early in their disease course and be managed by a clinical specialist knowledgeable in immune tolerance induction in Pompe disease to optimize treatment. Immune tolerance induction administered prior to and in conjunction with initiation of alglucosidase alfa has been reported to aid tolerability of alglucosidase alfa in CRIM-negative patients. CRIM status has been shown to be associated with immunogenicity and patients’ responses to enzyme replacement therapies. CRIM-negative infants with infantile-onset Pompe disease treated with alglucosidase alfa have shown poorer clinical response in the presence of high sustained IgG antibody titers and positive inhibitory antibodies compared to CRIM-positive infants [see ADVERSE REACTIONS].
Infusion reactions occurred in 20 of 39 (51%) patients treated with MYOZYME in clinical studies [see ADVERSE REACTIONS]. 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 pretreated 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]. 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 readministered MYOZYME.
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.
Testing services for antibodies against alglucosidase alfa are available through Genzyme Corporation. Contact Genzyme Corporation at 1-800-745-4447 for information on testing.
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.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic potential have not been performed with MYOZYME.
MYOZYME at intravenous doses up to 40 mg/kg, administered every other day (plasma AUC of 64.6 mg•min/mL, 0.4 times the human steady-state exposure at the recommended biweekly dose) had no effect on fertility and reproductive performance in mice.
Use In Specific Populations
Data from postmarketing reports and published case reports with alglucosidase alfa use in pregnant women have not identified a MYOZYME-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. The continuation of treatment for Pompe disease during pregnancy should be individualized to the pregnant woman. Untreated Pompe disease may result in worsening disease symptoms in pregnant women [see Clinical Considerations].
Reproduction studies performed in mice and rabbits at doses resulting in exposures up to 0.4 or 0.5 times the human steady-state AUC (area under the plasma concentration-time curve), respectively, during the period of organogenesis revealed no evidence of effects on embryo-fetal development. In mice there was an increase in pup mortality during lactation at maternal exposures 0.4 times the human steady-state AUC [see Data].
The estimated background risk of major birth defects and miscarriage in the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Pregnant women and women of reproductive potential should be encouraged to enroll in the Pompe patient registry. The registry will monitor the effect of MYOZYME on pregnant women and their offspring. For more information, visit www.registrynxt.com or call 1-800-745-4447, extension 15500.
Disease-associated maternal and/or embryo-fetal risk
Untreated Pompe disease has been associated with worsening respiratory and musculoskeletal symptoms in some pregnant women.
All reproductive studies included pretreatment with diphenhydramine to prevent or minimize hypersensitivity reactions. The effects of alglucosidase alfa were evaluated based on comparison to a control group treated with diphenhydramine alone. Daily intravenous administration of alglucosidase alfa up to 40 mg/kg in mice and rabbits (0.4 and 0.5 times the human steady-state AUC, respectively, at the recommended biweekly dose) during the period of organogenesis had no effects on embryo-fetal development. Administration of 40 mg/kg intravenously every other day in mice (0.4 times the human steady-state AUC at the recommended biweekly dose) during the period of organogenesis through lactation produced an increase in mortality of offspring during the lactation period.
Available published literature suggests the presence of alglucosidase alfa in human milk. There are no reports of adverse effects of alglucosidase alfa on the breastfed infant. There is no information on the effects of alglucosidase alfa on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for MYOZYME and any potential adverse effects on the breastfed child from MYOZYME or from the underlying maternal condition.
Lactating women with Pompe disease treated with MYOZYME should be encouraged to enroll in the Pompe disease registry [see Pregnancy].
A lactating woman may consider interrupting breastfeeding, pumping and discarding breast milk during treatment and for 24 hours after MYOZYME administration in order to minimize drug exposure to a breastfed infant.
Pediatric patients aged 1 month to 3.5 years at time of first infusion have been treated with MYOZYME in clinical trials [see Clinical Studies]. Other open-label clinical trials of MYOZYME have been performed in older pediatric patients ranging from 2 to 16 years at the initiation of treatment (juvenile-onset Pompe disease); however, the risks and benefits of MYOZYME treatment have not been established in the juvenile-onset Pompe disease population.
Clinical studies did not include any subjects aged 65 years and older. It is not known whether they respond differently than younger subjects [see Clinical Studies].