Recombinant human alglucosidase alfa (rhGAA; Myozyme, Lumizyme) is an enzyme replacement therapy for endogenous acid alpha-glucosidase. Myozyme and Lumizyme, produced by recombinant DNA technology in a Chinese hamster ovary cell line, are used in the treatment of Pompe disease (glycogen storage disease type II, GSD II). Pompe disease, a rare disease affecting approximately 1:40,000 (an estimated 5,000-10,000 people worldwide), is caused by a genetic deficiency of the enzyme acid alpha-glucosidase, which is responsible for breaking down glycogen within lysosomes, resulting in intralysosomal accumulation of glycogen. In infantile-onset Pompe disease, where the deficiency in acid alpha-glucosidase is absolute, accumulation of glycogen occurs primarily in the cardiac, hepatic, and skeletal muscles leading to cardiomyopathy, progressive muscle weakness, and impairment of respiratory function. In late-onset Pompe disease, a less aggressive type with relative deficiency of acid alpha-glucosidase, accumulation of glycogen is limited primarily to the skeletal muscles, which leads to progressive muscle weakness and eventual confinement to a wheelchair and respiratory failure; severe cardiac involvement is rarely apparent in the late-onset form. For both types of Pompe disease, respiratory failure is the usual cause of death; without treatment, the infantile-onset type is rapidly lethal by the age of 1 whereas death in patients with late-onset Pompe disease ranges from early childhood to late adulthood depending on the rate of disease progression. In a study of infants and children with advanced Pompe disease, both survival and ventilation-free survival at week 104 were prolonged among patients that were 3-43 months of age at initiation of alglucosidase 20 mg/kg IV every 2 weeks. Clinical response is dependent on residual muscle function at the start of treatment; patients with the best clinical response tend to be those treated early in the disease process before significant muscular deterioration occurs. Alglucosidase alfa was designated as an orphan drug for the treatment of Pompe disease in 1997; alglucosidase alfa (Myozyme) was approved by the FDA for the treatment of infantile-onset Pompe disease in April 2006. Lumizyme was approved by the FDA for patients 8 years and older with late (non-infantile) onset Pompe disease who do not have evidence of cardiac hypertrophy in May 2010; in August 2014, FDA approval was expanded to include all patients with Pompe disease.
General Administration Information
For storage information, see the specific product information within the How Supplied Section.
NOTE: If patients develop an infusion reaction, the infusion rate should be decreased or stopped temporarily; administration of antihistamines and/or antipyretics may alleviate some of the symptoms. If severe infusion reactions occur, including hypersensitivity reactions or anaphylaxis, discontinue the infusion immediately; appropriate supportive measures should be instituted.
NOTE: Patients can be pretreated with antihistamines, antipyretics, and/or corticosteroids approximately 30 minutes prior to each infusion; however, data on the effectiveness of pretreatment in the prevention of infusion-related reactions are conflicting.
Route-Specific Administration
Injectable Administration
Intravenous Administration
Reconstitution
-Do not use filter needles during preparation.
-Calculate the required dose and number of vials to be diluted by multiplying the patient's weight by 20 mg/kg and dividing by 50. Round up to the nearest whole vial.
-Remove the required number of vials from the refrigerator and allow them to reach room temperature (approximately 30 minutes).
-Using aseptic technique, slowly, in a drop-wise manner, inject 10.3 mL of Sterile Water for Injection to the inside wall of each vial; avoid foaming. Do not inject the Sterile Water for Injection directly onto the lyophilized cake. Tilt and roll each vial gently. Do not invert, swirl, or shake. Once reconstituted, each vial contains 50 mg of alglucosidase alfa at a final concentration of 5 mg/mL. Discard any unused product.
-Immediately inspect the reconstituted vials for particulate matter and discoloration. Do not use if opaque particles or discoloration are present. However, following reconstitution, alglucosidase alfa particles, which appear as thin white strands or translucent fibers are possible (usually less than 10/vial). These particles are removed via in-line filtration during infusion and do not have a detectable effect on the purity or strength.
-Storage: If immediate use is not possible, the reconstituted solution is stable for up to 24 hours refrigerated at 2 to 8 degrees C (36 to 46 degrees F). Storage at room temperature is not recommended. Protect from light. Do not freeze.
Dilution
-Dilute the solution in 0.9% Sodium Chloride Injection immediately after reconstitution to a final alglucosidase alfa concentration of 0.5 to 4 mg/mL.
-Prior to injecting the reconstituted alglucosidase alfa into the 0.9% Sodium Chloride Injection, remove airspace from the infusion bag to minimize particle formation. Alglucosidase alfa is sensitive to air-liquid interfaces.
-Slowly withdraw the reconstituted solution from each vial. Avoid foaming in the syringe. Inject the reconstituted alglucosidase alfa slowly and directly into the 0.9% Sodium Chloride Injection. Do not add directly into airspace that may remain within the infusion bag. Avoid foaming in the infusion bag. Gently invert or massage the infusion bag to mix. Do not shake.
-Storage: Administer without delay. If immediate use is not possible, the diluted solution is stable for up to 24 hours refrigerated at 2 to 8 degrees C (36 to 46 degrees F). Protect from light. Do not freeze.
Intravenous infusion
-Administer via intravenous (IV) infusion only.
-The diluted IV infusion solution should be filtered through a 0.2 micrometer, low protein-binding, in-line filter during administration so that visible particles are removed.
-Do not infuse in the same intravenous line with other products.
-Administer the diluted IV infusion solution over 4 hours.
-The initial infusion rate of 1 mg/kg/hour may be increased by 2 mg/kg/hour every 30 minutes, as tolerated. Measure vital signs at the end of each step. If vital signs are stable, the rate can be titrated to a maximum of 7 mg/kg/hour. The maximum rate is then maintained for the duration of the infusion.
-For patients weighing 1.25 to 2.5 kg: The total infusion volume = 25 mL. To achieve a dose of 1 mg/kg/hour, the infusion rate is 1.25 mL/hour; for a dose of 3 mg/kg/hour, the infusion rate is 3.75 mL/hour; for a dose of 5 mg/kg/hour, the infusion rate is 6.25 mL/hour; and for a dose of 7 mg/kg/hour, the infusion rate is 6.6 mL/hour.
-For patients weighing 2.6 to 10 kg: The total infusion volume = 50 mL. To achieve a dose of 1 mg/kg/hour, the infusion rate is 3 mL/hour; for a dose of 3 mg/kg/hour, the infusion rate is 8 mL/hour; for a dose of 5 mg/kg/hour, the infusion rate is 13 mL/hour; and for a dose of 7 mg/kg/hour, the infusion rate is 18 mL/hour.
-For patients weighing 10.1 to 20 kg: The total infusion volume = 100 mL. To achieve a dose of 1 mg/kg/hour, the infusion rate is 5 mL/hour; for a dose of 3 mg/kg/hour, the infusion rate is 15 mL/hour; for a dose of 5 mg/kg/hour, the infusion rate is 25 mL/hour; and for a dose of 7 mg/kg/hour, the infusion rate is 35 mL/hour.
-For patients weighing 20.1 to 30 kg: The total infusion volume = 150 mL. To achieve a dose of 1 mg/kg/hour, the infusion rate is 8 mL/hour; for a dose of 3 mg/kg/hour, the infusion rate is 23 mL/hour; for a dose of 5 mg/kg/hour, the infusion rate is 38 mL/hour; and for a dose of 7 mg/kg/hour, the infusion rate is 53 mL/hour.
-For patients weighing 30.1 to 35 kg: The total infusion volume = 200 mL. To achieve a dose of 1 mg/kg/hour, the infusion rate is 10 mL/hour; for a dose of 3 mg/kg/hour, the infusion rate is 30 mL/hour; for a dose of 5 mg/kg/hour, the infusion rate is 50 mL/hour; and for a dose of 7 mg/kg/hour, the infusion rate is 70 mL/hour.
-For patients weighing 35.1 to 50 kg: The total infusion volume = 250 mL. To achieve a dose of 1 mg/kg/hour, the infusion rate is 13 mL/hour; for a dose of 3 mg/kg/hour, the infusion rate is 38 mL/hour; for a dose of 5 mg/kg/hour, the infusion rate is 63 mL/hour; and for a dose of 7 mg/kg/hour, the infusion rate is 88 mL/hour.
-For patients weighing 50.1 to 60 kg: The total infusion volume = 300 mL. To achieve a dose of 1 mg/kg/hour, the infusion rate is 15 mL/hour; for a dose of 3 mg/kg/hour, the infusion rate is 45 mL/hour; for a dose of 5 mg/kg/hour, the infusion rate is 75 mL/hour; and for a dose of 7 mg/kg/hour, the infusion rate is 105 mL/hour.
-For patients weighing 60.1 to 100 kg: The total infusion volume = 500 mL. To achieve a dose of 1 mg/kg/hour, the infusion rate is 25 mL/hour; for a dose of 3 mg/kg/hour, the infusion rate is 75 mL/hour; for a dose of 5 mg/kg/hour, the infusion rate is 125 mL/hour; and for a dose of 7 mg/kg/hour, the infusion rate is 175 mL/hour.
-For patients weighing 100.1 to 120 kg: The total infusion volume = 600 mL. To achieve a dose of 1 mg/kg/hour, the infusion rate is 30 mL/hour; for a dose of 3 mg/kg/hour, the infusion rate is 90 mL/hour; for a dose of 5 mg/kg/hour, the infusion rate is 150 mL/hour; and for a dose of 7 mg/kg/hour, the infusion rate is 210 mL/hour.
-For patients weighing 120.1 to 140 kg: The total infusion volume = 700 mL. To achieve a dose of 1 mg/kg/hour, the infusion rate is 35 mL/hour; for a dose of 3 mg/kg/hour, the infusion rate is 105 mL/hour; for a dose of 5 mg/kg/hour, the infusion rate is 175 mL/hour; and for a dose of 7 mg/kg/hour, the infusion rate is 245 mL/hour.
-For patients weighing 140.1 to 160 kg: The total infusion volume = 800 mL. To achieve a dose of 1 mg/kg/hour, the infusion rate is 40 mL/hour; for a dose of 3 mg/kg/hour, the infusion rate is 120 mL/hour; for a dose of 5 mg/kg/hour, the infusion rate is 200 mL/hour; and for a dose of 7 mg/kg/hour, the infusion rate is 280 mL/hour.
-For patients weighing 160.1 to 180 kg: The total infusion volume = 900 mL. To achieve a dose of 1 mg/kg/hour, the infusion rate is 45 mL/hour; for a dose of 3 mg/kg/hour, the infusion rate is 135 mL/hour; for a dose of 5 mg/kg/hour, the infusion rate is 225 mL/hour; and for a dose of 7 mg/kg/hour, the infusion rate is 315 mL/hour.
-For patients weighing 180.1 to 200 kg: The total infusion volume = 1,000 mL. To achieve a dose of 1 mg/kg/hour, the infusion rate is 50 mL/hour; for a dose of 3 mg/kg/hour, the infusion rate is 150 mL/hour; for a dose of 5 mg/kg/hour, the infusion rate is 250 mL/hour; and for a dose of 7 mg/kg/hour, the infusion rate is 350 mL/hour.
Serious hypersensitivity reactions or anaphylaxis, including acute cardiorespiratory failure, may occur both during and within 3 hours after alglucosidase alfa infusion. Severe hypersensitivities may present as respiratory distress, hypoxia, apnea, dyspnea, bradycardia (21%), sinus tachycardia (8% to 23%), bronchospasm, throat tightness (3%), hypotension, angioedema (including tongue or lip swelling, periorbital edema, and face edema), and urticaria (8% to 21%). During clinical trials in late-onset Pompe disease patients (n = 60), anaphylaxis occurred in 7% of patients. In clinical trials and postmarketing safety experience with Myozyme, approximately 1% of patients developed anaphylactic shock and/or cardiac arrest during alglucosidase alfa infusion. Appropriate medical support including cardiopulmonary resuscitation equipment should be readily available upon alglucosidase alfa administration. If anaphylaxis or severe hypersensitivity reactions occur, immediately discontinue the infusion and initiate appropriate medical treatment (e.g., antihistamines, corticosteroids, epinephrine, IV fluids, oxygen). Consider the risks and benefits of re-administering alglucosidase alfa after a severe allergic reaction. Some patients have been re-challenged and have continued to receive the drug under close clinical supervision. Consider testing for IgG titers if a patient develops a hypersensitivity reaction; monitor all patients for the formation of IgG antibodies every 3 months for 2 years and then annually thereafter. Patients who experience anaphylactic or allergic 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 higher risk for hypersensitivity and therefore should be monitored closely during administration using lower starting doses and slower infusion rates. There are currently no marketed tests for antibodies against alglucosidase alfa; however, a testing service is provided by Genzyme. Call 1-800-745-4447 for information on testing and to obtain a sample collection box.
The most commonly reported adverse reactions to alglucosidase alfa are infusion-related hypersensitivity reactions, which occurred in 51% of patients during clinical trials. Infusion-related reactions involving at least 2 of 3 body systems (cutaneous, respiratory, or cardiovascular) have been reported in at least 14% of patients treated with alglucosidase alfa (Myozyme) during clinical trials or expanded access programs. Overall, reactions occurring in 5% or more of patients included rash, fever, flushing, urticaria, headache, hyperhidrosis, nausea, cough, decreased oxygen saturation, tachypnea, chest discomfort, dizziness, muscle cramps/twitching, agitation, cyanosis, erythema, hypertension, pallor, rigors, tremor, vomiting, fatigue, and myalgia. Specifically, reactions were reported as follows in infantile-onset trials for Lumizyme (n = 39): fever (15%), rash (including erythematous, macular, and maculopapular rash) (18%), urticaria (13%), flushing (13%), hypertension (10%), decreased oxygen saturation (8%), cough (8%), tachypnea (8%), erythema (5%), vomiting (5%), rigors (5%), pallor (5%), cyanosis (5%), agitation (5%), and tremor (5%); of note, higher incidences of fever (92%), rash (54%), urticaria (21%), flushing (21%), decreased oxygen saturation (41%), cough (46%), tachypnea (23%), and vomiting (49%) were observed during Myozyme trials (n = 39) as well as diarrhea (62%) and upper abdominal pain (15%). Additional hypersensitivity reactions observed in infantile-onset Pompe disease patients include livedo reticularis, irritability, retching, increased lacrimation, rales, respiratory tract infection, and cold sweat. In late-onset trials (n = 60), hyperhidrosis (8%), urticaria (8%), chest discomfort (7%), muscle twitching (7%), myalgia (5%), flushing (5%), hypertension (5%), vomiting (5%), peripheral edema (3%), pruritus (3%), and papular rash (3%) were reported; paresthesias, local swelling, headache, and diarrhea were also reported in 3% or more of patients. Such reactions may occur at any time during or up to 2 hours after infusion and are more likely with higher infusion rates. Delayed reactions (e.g., hyperhidrosis, fatigue, myalgia, nausea) may occur up to 48 hours after infusion completion; counsel patients about the possibility of delayed onset infusion reactions and give them proper follow-up instructions. Patients pre-treated with antihistamines, antipyretics, and/or corticosteroids may still experience reactions. Closely observe patients during and after drug administration and be prepared to manage hypersensitivity or infusion-related reactions; appropriate medical support, including cardiopulmonary resuscitation equipment should be readily available. Symptoms of infusion-related reactions may be ameliorated by decreasing the infusion rate, temporarily stopping the infusion, and/or administering antihistamines and/or antipyretics. If severe infusion-related or hypersensitivity reactions occur, immediately discontinue the alglucosidase alfa infusion and initiate appropriate medical treatment. After infusion completion, a flu-like illness or a combination of events such as fever, chills, myalgia, arthralgia, pain, or fatigue has been observed in some patients, usually lasting for 1 to 3 days. If such a reaction occurs, most patients can be successfully re-challenged using lower doses and/or pre-treatment with anti-inflammatory drugs and/or corticosteroids, but careful monitoring is required. Multiple incidences of wheezing, seizures, peripheral coldness, restlessness, nervousness, back pain, stridor, pharyngeal edema, abdominal pain, muscle spasm, and conjunctivitis have also been reported during postmarketing use. In addition, a case of hyperparathyroidism has been reported.
Cardiac arrhythmias (e.g., ventricular fibrillation, ventricular tachycardia, bradycardia) requiring resuscitation and/or defibrillation or resulting in cardiac arrest or death have been observed in patients with infantile-onset Pompe disease and cardiomyopathy undergoing general anesthesia. Use caution when administering general anesthesia for any reason, including the placement of a central venous catheter intended for alglucosidase alfa infusion. Chest pain (unspecified) has been reported in 7% of late-onset Pompe disease patients during clinical trials. One patient with a history of Wolff-Parkinson-White syndrome developed supraventricular tachycardia (SVT).
Acute heart failure and respiratory arrest requiring intubation and inotropic support have been observed up to 3 days after infusion with alglucosidase alfa in patients with infantile-onset Pompe disease and underlying cardiomyopathy. Respiratory distress (33%) and failure (31%) have been reported during infantile-onset trials. Cardiorespiratory failure may be associated with fluid overload from the administration of alglucosidase alfa; patients should receive alglucosidase alfa therapy in the recommend volume and at the recommended rate. Patients with acute or chronic cardiac and/or respiratory compromise may be at greater risk for acute cardiorespiratory failure and require additional monitoring. Have appropriate medical support and monitoring measures readily available during the alglucosidase alfa infusion. Prolonged observation times may be needed for infants with cardiac dysfunction.
Infection-related events, including catheter-related infection (28%), respiratory syncytial virus (greater than 10%), otitis media (44%), ear infection (33%), pneumonia (46%), gastroenteritis (41%), upper respiratory tract infection (44%), pharyngitis (36%), nasopharyngitis (23%), oral candidiasis (31%), and bronchiolitis (23%) were among the most commonly reported treatment-emergent events associated with alglucosidase alfa during infantile-onset clinical trials of Myozyme. Other commonly reported events include diaper dermatitis (36%), constipation (23%), gastroesophageal reflux (26%), rhinorrhea (28%), post-procedural pain (26%), and anemia (31%). Among juvenile-onset patients (age range: 5 to 15 years), pharyngitis (9%), malaise (6%), and rhinitis (6%) were among the most common adverse reactions reported.
As with all therapeutic proteins, there is a potential for immunogenicity. In clinical trials, the majority of patients (90% or more) tested positive for IgG antibody formation to alglucosidase alfa, typically within 3 months of treatment. No apparent association between mean or peak IgG antibody titers and adverse reaction occurrence was noted. However, evidence suggests some patients who develop sustained IgG antibody titers of 12,800 or more may experience reduced clinical efficacy to alglucosidase treatment, such as loss of motor function, ventilator dependence, or death, possibly due to increased enzyme clearance. Patients receiving alglucosidase alfa who experience a loss of motor function should be tested for neutralization of enzyme uptake or activity. During Lumizyme trials, antibody titers for cellular uptake inhibition were present in 18 of 59 (31%) patients by week 78 of therapy. Patients who were positive for uptake inhibition tended to have higher IgG titers than patients who tested negative for uptake inhibition. The clearance values of alglucosidase alfa were approximately 1.2- to 1.8-fold greater in the presence of inhibitory antibodies as compared to in the absence of inhibitory antibodies. Additionally, hypersensitivity reactions may be more common in patients with antibodies to alglucosidase alfa. Patients who develop IgE antibodies to alglucosidase alfa appear to be at a higher risk for anaphylaxis and severe allergic reactions; monitor these patients more closely during alglucosidase alfa receipt. Some patients who tested positive were successfully re-challenged using a slower infusion rate at lower initial doses. Patients should be monitored for IgG antibody formation every 3 months for 2 years and annually thereafter. Testing for IgG titers may also be considered if patients develop hypersensitivity reactions, immune-mediated reactions, or lose clinical response. Patients who experience decreased clinical efficacy may also be tested for inhibitory activity. Those who experience anaphylactic or hypersensitivity reactions may also be tested for IgE antibodies to alglucosidase alfa and other mediators of anaphylaxis. Contact Genzyme Corporation at 1-800-745-4447 to obtain testing information and to obtain a sample collection box; no marketed tests for antibodies against alglucosidase alfa exist.
Immune-mediated reactions presenting as proteinuria and nephrotic syndrome have occurred in some patients after alglucosidase alfa treatment. Systemic reactions, including possible type III immune-mediated reactions have been observed several weeks to 3 years after treatment initiation. Nephrotic syndrome secondary to membranous glomerulonephritis has been observed in some Pompe disease patients with persistently positive anti-hrGAA IgG antibody titers. In response to clinical deterioration, a patient with Pompe disease and significant anti-recombinant human acid alpha-glucosidase (rhGAA) antibodies underwent an experimental immune tolerance regimen consisting of high doses of rhGAA. After 10 months of 5 times/week rhGAA therapy, the patient developed nephrotic syndrome; a kidney biopsy showed deposition of glomerular immune complexes containing rhGAA. rhGAA was stopped temporarily, and then reinstituted at a reduced dose; the nephrotic syndrome resolved over a period of 5 months. Dose reduction appears to help by minimizing the antigenic load to the kidney, allowing time for resolution. Patients receiving alglucosidase alfa should undergo periodic urinalysis and be monitored for the development of immune-related reactions. If such reactions occur, initiate appropriate medical treatment and consider therapy discontinuation. The risks and benefits of re-administering algluosidase alfa after a severe reaction should be considered; some patients have been re-challenged and have continued to receive therapy under close medical supervision and extreme care. Patients should be monitored for IgG antibody formation every 3 months for 2 years and then annually thereafter. If a patient develops an immune-mediated reaction, consider testing for IgG titers and for IgE antibodies to alglucosidase alfa.
Severe cutaneous and systemic immune mediated reactions including ulcerative and necrotizing skin lesions (skin ulcer and skin necrosis) and possible type III immune complex-mediated reactions have been observed with alglucosidase alfa. These reactions occurred several weeks to 3 years after alglucosidase alfa initiation. Deposition of anti-rhGAA antibodies in the skin lesion was noted in 1 patient. Another patient developed severe inflammatory arthropathy in association with fever and elevated erythrocyte sedimentation rate. Monitor patients receiving alglucosidase alfa for the development of systemic immune complex-mediated reactions involving skin and other organs. If immune mediated reactions occur, consider alglucosidase alfa discontinuation and initiate appropriate medical treatment. The risks and benefits of re-administering algluosidase alfa after a severe reaction should be considered; some patients have successfully been re-challenged and have continued to receive therapy under close clinical supervision. Patients should be monitored for IgG antibody formation every 3 months for 2 years and then annually thereafter. If a patient develops a hypersensitivity or other immune-mediated reaction, consider testing for IgG titers and for IgE antibodies to alglucosidase alfa.
Because alglucosidase alfa is a therapeutic protein, there is the potential for immunogenicity. In clinical trials, the majority of patients developed alglucosidase alfa-specific IgG antibodies, usually within 3 months of treatment initiation. There is evidence to suggest some patients who develop high and sustained IgG antibody titers may experience reduced clinical efficacy to alglucosidase alfa treatment including loss of motor function, ventilator dependence, and death. Furthermore, Cross Reactive Immunologic Material (CRIM)-negative infants have shown reduced clinical effect in the presence of high sustained IgG antibody titers with inhibitory activity. Patients should be monitored for IgG antibody formation every 3 months for 2 years and then annually thereafter. Patients with a loss of clinical response may also be tested for IgG titers and inhibitory antibody activity.
In Cynomolgus monkeys who received 1.6-3.2 times the recommended human alglucosidase alfa dose based on body surface area, alpha-glucosidase concentrations were above background concentrations in liver tissue several days after the last dose. No concurrent changes in liver enzymes or histopathology were observed in the monkeys. However, because of these findings, monitoring of liver function tests (LFTs) is recommended before Myozyme initiation and periodically thereafter. According to the manufacturer, exercise care when interpreting LFT results, as aspartate aminotransferase and alanine aminotransferase concentrations may be raised as a result of the muscle pathology in patients with Pompe disease.
Serious hypersensitivity reactions or anaphylaxis have been observed in patients during and up to 3 hours after alglucosidase alfa infusion. Some of the reactions were severe or life-threatening and included anaphylactic shock, cardiac arrest, respiratory arrest, hypoxia, apnea, dyspnea, bradycardia, tachycardia, bronchospasm, throat tightness, hypotension, angioedema, and urticaria. Infusion-related reactions may occur at any time during or for up to 3 hours after the infusion of alglucosidase alfa and are more likely to occur with higher infusion rates. Closely observe patients during and after drug administration and be prepared to manage alglucosidase alfa hypersensitivity or infusion-related reactions; appropriate medical support, including cardiopulmonary resuscitation equipment, should be readily available. Symptoms of mild to moderate infusion-related reactions may be ameliorated by decreasing the infusion rate, temporarily stopping the infusion, and/or administering antihistamines and/or antipyretics. If severe infusion-related or hypersensitivity reactions occur, immediately discontinue the alglucosidase alfa infusion and initiate appropriate medical treatment. Immune-mediated reactions presenting as proteinuria, nephrotic syndrome, and necrotizing skin lesions have also occurred in some patients after alglucosidase treatment. Systemic reactions, including possible type III immune-mediated reactions, have been observed several weeks to 3 years after treatment initiation. A cross-reactive immunologic material (CRIM) assessment should be performed early in the disease course in patients with infantile-onset Pompe disease. Immune tolerance induction administered prior to and in conjunction with alglucosidase alfa may increase tolerability of alglucosidase alfa in CRIM-negative patients. CRIM-negative infants with infantile-onset Pompe disease treated with alglucosidase alfa have poorer clinical outcomes in the presence of high and sustained IgG antibody titers and positive inhibitory antibodies compared to CRIM-positive infants. Immune tolerance induction should be administered under the management of a clinical specialist trained in immune tolerance induction in Pompe disease. In clinical studies, most patients developed IgG antibodies to alglucosidase alfa within 3 months of treatment. Some patients who develop high and sustained IgG antibody titers, including CRIM-negative patients, may experience reduced clinical alglucosidase alfa treatment efficacy, such as loss of motor function, ventilator dependence, or death. Patients receiving alglucosidase alfa should undergo periodic urinalysis and be monitored for the development of immune-related reactions involving the skin or other organs. If immune-mediated reactions occur, initiate appropriate medical treatment, and consider therapy discontinuation. Patients should be informed of the signs and symptoms of hypersensitivity and immune-mediated reactions and instructed to seek immediate medical attention should they occur. The risks and benefits of re-administering alglucosidase alfa after a severe reaction should be considered; some patients have been re-challenged and have continued to receive therapy under close medical supervision and extreme care. Pre-treatment with antihistamines, antipyretics, and/or steroids may prevent some infusion-related reactions, although the data regarding the efficacy of pre-treatment are conflicting. Patients should be monitored for IgG antibody formation every 3 months for 2 years and then annually thereafter. If a patient develops a hypersensitivity or other immune-mediated reaction, consider testing for IgG titers and for IgE antibodies to alglucosidase alfa.
Patients with advanced Pompe disease often have underlying compromised cardiac and respiratory function and should be monitored more closely than other patients during use of alglucosidase alfa. Acute cardiorespiratory failure (heart failure and respiratory insufficiency) requiring intubation and inotropic support has been observed up to 3 days after infusion in infantile-onset Pompe disease patients with pre-existing cardiac hypertrophic cardiomyopathy. Any patients with compromised cardiac and/or respiratory function (e.g., cardiac disease, heart failure, respiratory insufficiency, respiratory illness, sepsis) may be at risk for serious acute exacerbation of their cardiac or respiratory status due to fluid overload. These patients require additional monitoring. Appropriate medical support and monitoring should be readily available during each infusion, and some patients may require prolonged observation times that should be based on the individual patient needs. Careful consideration should be given to the patient's clinical status prior to the administration of alglucosidase alfa. In addition, the administration of general anesthesia can be complicated by the presence of severe cardiac disease and skeletal muscle disease, including respiratory muscle weakness. Exercise caution when administering general anesthesia for any reason, including surgery or the placement of a central venous catheter intended for alglucosidase alfa infusion. Ventricular arrhythmias and bradycardia, resulting in cardiac arrest and death, or requiring cardiac resuscitation or defibrillation have been observed in infantile-onset Pompe disease patients with cardiac hypertrophy.
There are no adequate prospective studies of alglucosidase alfa in pregnant women. However, data from postmarketing reports and published case reports have not identified an alglucosidase alfa associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Individualize the treatment for Pompe disease during pregnancy to the affected woman; untreated Pompe disease may result in worsening disease symptoms in pregnant women. Daily administration of intravenous alglucosidase alfa up to 40 mg/kg/day in mice and rabbits (0.4 and 0.5 times the human steady-state exposure, respectively, at the recommended bi-weekly dose) during the period of organogenesis had no effects on embryo-fetal development. An increase in pup mortality during the lactation period was observed when alglucosidase alfa 40 mg/kg/day was administered every other day in mice during the period of organogenesis through lactation. Alglucosidase alfa should only be used during pregnancy if the potential benefit justifies the potential risk. Literature suggests the use of the drug is compatible with pregnancy. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to alglucosidase alfa; information about the registry can be obtained at www.registrynxt.com or by calling 1-800-633-1610 or 1-800-745-4447 (extension 15500).
Alglucosidase alfa is present in human milk. In a case report, the enzymatic activity of alglucosidase alfa was detected in the breast milk of a lactating woman up to 24 hours after the end of intravenous administration. To minimize infant exposure, experts have recommended the nursing mother temporarily pump and discard breast milk produced during the 24 hours after drug administration. This case report, along with other literature, suggests that with careful management, the enzyme replacement therapy is compatible with breast-feeding. In another case report, a 38-year-old woman interrupted alglucosidase alfa therapy during pregnancy but restarted treatment with 20 mg/kg every 2 weeks during her first postpartum month. The patient expressed additional milk before alglucosidase therapy since she received strict advice that breast-feeding was not allowed for 24 hours after the completion of drug infusion; at 10 months, the nursing infant was developing normally. Data continue to be collected via a registry. Lactating women are encouraged to enroll in the Pompe Registry by calling 1-800-745-4447 (extension 15500) in the U.S. or online at www.lumizyme.com/patients/resources/the_pompe_registry.
Clinical studies of alglucosidase alfa did not include sufficient numbers of geriatric patients > 65 years of age to determine whether they respond to the drug differently from younger patients.
The safety and effectiveness of alglucosidase alfa have been established in pediatric patients with Pompe disease. Alglucosidase alfa (Lumizyme) has been shown to improve ventilator-free survival in neonates, infants, and young children with infantile-onset Pompe disease (age at first infusion: 0.2 months to 3.5 years). Lumizyme may be used in all patients with Pompe disease, regardless of the age of disease onset. Careful consideration should be given to the pediatric patient's clinical status before administration. Cardiac hypertrophy and respiratory muscle weakness are common in young pediatric patients with Pompe disease. Appropriate medical support (e.g., cardiopulmonary resuscitation equipment, adequately trained staff) and careful, perhaps prolonged, monitoring are required with each infusion. Hypersensitivity reactions, anaphylaxis, and acute cardiorespiratory failure have occurred in pediatric patients receiving alglucosidase alfa. Acute cardiorespiratory failure is most likely associated with fluid overload in patients with infantile-onset Pompe disease and underlying cardiac hypertrophy. Also, cardiac arrhythmia and sudden cardiac death have occurred in such patients during general anesthesia for central venous catheter placement.
For the treatment of acid alpha-glucosidase deficiency (Pompe disease):
NOTE: Alglucosidase alfa was designated as an orphan drug for the treatment of Pompe disease in 1997.
NOTE: Initiation of alglucosidase alfa therapy in the earliest stages of the disease process is associated with the most clinical benefit.
-for the treatment of infantile-onset acid alpha-glucosidase deficiency (Pompe disease):
Intravenous dosage:
Infants and Children: 20 mg/kg/dose IV administered over about 4 hours every 2 weeks. The total infusion volume is based on the patient's weight. The initial infusion rate should be no more than 1 mg/kg/hour with titrations of 2 mg/kg/hour every 30 minutes up to a maximum rate of 7 mg/kg/hour; measure vital signs at the end of each titration. Only increase the infusion rate if the patient is stable. If infusion reactions occur, the infusion may be slowed or temporarily stopped; if severe reactions occur, discontinue the infusion. Doses of 40 mg/kg IV once every 2 weeks have also been studied; however, no differences in outcomes between 20 mg/kg and 40 mg/kg IV are apparent.
Neonates: 20 mg/kg/dose IV administered over about 4 hours every 2 weeks. The total infusion volume is based on the patient's weight. The initial infusion rate should be no more than 1 mg/kg/hour with titrations of 2 mg/kg/hour every 30 minutes up to a maximum rate of 7 mg/kg/hour; measure vital signs at the end of each titration. Only increase the infusion rate if the patient is stable. If infusion reactions occur, the infusion may be slowed or temporarily stopped; if severe reactions occur, discontinue the infusion. Doses of 40 mg/kg IV once every 2 weeks have also been studied; however, no differences in outcomes between 20 mg/kg and 40 mg/kg IV are apparent.
-for the treatment of late-onset (non-infantile) acid alpha-glucosidase deficiency (Pompe disease) :
Intravenous dosage (Lumizyme only):
Adults: 20 mg/kg/dose IV administered over about 4 hours every 2 weeks. The total infusion volume is based on the patient's weight. The initial infusion rate should be no more than 1 mg/kg/hour with titrations of 2 mg/kg/hour every 30 minutes up to a maximum rate of 7 mg/kg/hour; measure vital signs at the end of each titration. Only increase the infusion rate if the patient is stable. If infusion reactions occur, the infusion may be slowed or temporarily stopped; if severe reactions occur, discontinue the infusion.
Children and Adolescents: 20 mg/kg/dose IV administered over about 4 hours every 2 weeks. The total infusion volume is based on the patient's weight. The initial infusion rate should be no more than 1 mg/kg/hour with titrations of 2 mg/kg/hour every 30 minutes up to a maximum rate of 7 mg/kg/hour; measure vital signs at the end of each titration. Only increase the infusion rate if the patient is stable. If infusion reactions occur, the infusion may be slowed or temporarily stopped; if severe reactions occur, discontinue the infusion.
Maximum Dosage Limits:
-Adults
20 mg/kg/dose IV every 2 weeks.
-Geriatric
Safety and efficacy have not been established.
-Adolescents
20 mg/kg/dose IV every 2 weeks.
-Children
20 mg/kg/dose IV every 2 weeks.
-Infants
20 mg/kg/dose IV every 2 weeks.
-Neonates
20 mg/kg/dose IV every 2 weeks.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
There are no drug interactions associated with Alglucosidase alfa products.
Recombinant human alglucosidase alfa provides exogenous human lysosomal acid alpha-glucosidase; alglucosidase alfa is used primarily in patients with Pompe disease, which is an inherited disorder of glycogen metabolism caused by the relative or absolute absence of acid alpha-glucosidase. Deficiency in acid alpha-glucosidase results in accumulation of lysosomal glycogen both in tissues and intracellularly; the most commonly affected cells are cardiac, skeletal, and smooth muscle. Accumulation of glycogen leads to the development of cardiomyopathy, progressive muscle weakness, and impairment of respiratory function. Treatment with alglucosidase is associated with prolonging life by improving cardiac, respiratory, and skeletal muscle function. In general, alglucosidase alfa will have the most beneficial effects when initiated in those patients without extensive muscle deterioration.
Once available systemically, alglucosidase alfa mimics endogenous acid alpha-glucosidase. Alglucosidase alfa binds to the mannose-6-phosphate receptors on cellular surfaces and is internalized and transported into lysosomes. Once in the lysosome, alglucosidase alfa undergoes proteolytic cleavage resulting in increased enzymatic activity and cleavage of glycogen.
Alglucosidase alfa is administered via intravenous infusion over 4 hours or longer.
-Route-Specific Pharmacokinetics
Intravenous Route
After intravenous administration, alglucosidase alfa binds to mannose-6-phosphate receptors on cellular surfaces; alglucosidase alfa is internalized and transported to lysozymes, where it undergoes proteolytic cleavage and exerts its therapeutic effects. The pharmacokinetics of alglucosidase alfa were evaluated in 10 adult patients (age range: 19 to 57 years) receiving 20 mg/kg/dose as a 4-hour infusion. The estimated mean AUC was 1,890 mcg x hour/mL with 51% coefficient of variation (CV) and Cmax was 307 mcg/mL with 47% CV.
-Special Populations
Pediatrics
Infants and Children 1 month to 3.5 years
The pharmacokinetics of alglucosidase alfa were evaluated in 13 infants (age range: 1 to 7 months) receiving 20 mg/kg/dose as a 4-hour infusion or 40 mg/kg/dose as a 6.5-hour infusion every 2 weeks. Systemic exposure was approximately dose proportional. Based on blood samples from 5 patients receiving the 20 mg/kg dose, estimated mean AUC was 811 mcg x hour/mL with 17% coefficient of variation (CV), Cmax was 162 mcg/mL with 19% CV, clearance was 24 mL/kg/hour with 16% CV, and half-life was 2.3 hours with 17% CV. These parameters were similar to those observed for older patients (n = 14; age range: 6 months to 3.5 years) also receiving 20 mg/kg/dose as a 4-hour infusion every 2 weeks.
Infants and Children 7 months to 13 years
The pharmacokinetics of alglucosidase alfa were evaluated in 10 pediatric patients (age range: 7 months to 13 years) receiving 20 mg/kg/dose as a 4-hour infusion. The estimated mean AUC was 1,110 mcg x hour/mL with 68% CV and Cmax was 204 mcg/mL with 46% CV.
Other
Antibody titers
Some evidence suggests that patients who develop sustained anti-alglucosidase alfa antibody titers 12,800 or greater may have a poorer clinical response to treatment. Five patients with infantile-onset Pompe disease and antibody titers 12,800 or greater had an average increase in drug clearance of 50% (range: 5% to 90%) from week 1 to week 12 of treatment; patients without high concentrations of antibodies (e.g., titers less than 12,800) had similar clearance values at baseline and week 12. An approximate 1.2- to 1.8-fold increase in clearance was also observed at week 52 in 4 of 5 patients with late-onset Pompe disease who tested positive for antibodies that inhibit the cellular uptake of enzyme. Positive inhibitory antibody status correlated with higher IgG titers.