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Pompe Disease Agents
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.
Enzyme replacement therapyUsed to treat patients with acid alpha-glucosidase deficiency (Pompe disease, glycogen storage disease II)Myozyme FDA-approved for infantile-onset disease; Lumizyme FDA-approved for infantile- and late-onset disease
Lumizyme Intravenous Inj Pwd F/Sol: 52.5mg
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/hr with titrations of 2 mg/kg/hour every 30 minutes up to a maximum rate of 7 mg/kg/hour; vital signs should be measured at the end of each titration. The rate should be increased only 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. NOTE: Alglucosidase alfa should be administered through an in-line 0.22 micrometer filter.
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/hr with titrations of 2 mg/kg/hour every 30 minutes up to a maximum rate of 7 mg/kg/hour; vital signs should be measured at the end of each titration. The rate should be increased only if the patient is stable. If infusion reactions occur, the infusion may be slowed or temporarily stopped; if severe reactions occur, discontinue the infusion. NOTE: Alglucosidase alfa should be administered through an in-line 0.22 micrometer filter.
20 mg/kg/dose IV. The dose is administered once every 2 weeks.
Safety and efficacy have not been established.
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
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.
Administer via intravenous (IV) infusion only.Do not infuse in the same intravenous line with other products.Storage of reconstituted vials: Reconstituted vials should be further diluted immediately. If immediate dilution is not possible, the reconstituted vials can be stored for up to 24 hours under refrigeration at 2—8 degrees C (36—46 degrees F). Protect the reconstituted vials from light.Reconstitution and dilution: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 (SWI) to the inside wall of each vial; avoid foaming. Do not inject the SWI 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. Neither Myozyme nor Lumizyme contain preservatives; discard any unused product.Immediately, visually inspect the reconstituted vials for particulate matter and discoloration. Do not use if opaque particles or discoloration are present. However, following reconstitution or dilution, alglucosidase alfa particles, which appear as thin white strands or translucent fibers are possible (usually < 10/vial). These particles are removed via in-line filtration during infusion and do not have a detectable effect on the purity or strength.Further dilute the solution in 0.9% sterile sodium chloride for injection immediately after reconstitution, to a final alglucosidase alfa concentration of 0.5—4 mg/mL (see below).Prior to injecting the reconstituted alglucosidase alfa into the sodium chloride solution, 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 sodium chloride solution. 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.Protect the diluted solution from light. Intravenous infusion: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.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—10 kg: The total infusion volume = 50 mL. To achieve a dose of 1 mg/kg/hr, the infusion rate is 3 mL/hr; for a dose of 3 mg/kg/hr, the infusion rate is 8 mL/hr; for a dose of 5 mg/kg/hr, the infusion rate is 13 mL/hr; and for a dose of 7 mg/kg/hr, the infusion rate is 18 mL/hr.For patients weighing 10.1—20 kg: The total infusion volume = 100 mL. To achieve a dose of 1 mg/kg/hr, the infusion rate is 5 mL/hr; for a dose of 3 mg/kg/hr, the infusion rate is 15 mL/hr; for a dose of 5 mg/kg/hr, the infusion rate is 25 mL/hr; and for a dose of 7 mg/kg/hr, the infusion rate is 35 mL/hr.For patients weighing 20.1—30 kg: The total infusion volume = 150 mL. To achieve a dose of 1 mg/kg/hr, the infusion rate is 8 mL/hr; for a dose of 3 mg/kg/hr, the infusion rate is 23 mL/hr; for a dose of 5 mg/kg/hr, the infusion rate is 38 mL/hr; and for a dose of 7 mg/kg/hr, the infusion rate is 53 mL/hr.For patients weighing 30.1—35 kg: The total infusion volume = 200 mL. To achieve a dose of 1 mg/kg/hr, the infusion rate is 10 mL/hr; for a dose of 3 mg/kg/hr, the infusion rate is 30 mL/hr; for a dose of 5 mg/kg/hr, the infusion rate is 50 mL/hr; and for a dose of 7 mg/kg/hr, the infusion rate is 70 mL/hr.For patients weighing 35.1—50 kg: The total infusion volume = 250 mL. To achieve a dose of 1 mg/kg/hr, the infusion rate is 13 mL/hr; for a dose of 3 mg/kg/hr, the infusion rate is 38 mL/hr; for a dose of 5 mg/kg/hr, the infusion rate is 63 mL/hr; and for a dose of 7 mg/kg/hr, the infusion rate is 88 mL/hr.For patients weighing 50.1—60 kg: The total infusion volume = 300 mL. To achieve a dose of 1 mg/kg/hr, the infusion rate is 15 mL/hr; for a dose of 3 mg/kg/hr, the infusion rate is 45 mL/hr; for a dose of 5 mg/kg/hr, the infusion rate is 75 mL/hr; and for a dose of 7 mg/kg/hr, the infusion rate is 105 mL/hr.For patients weighing 60.1—100 kg: The total infusion volume = 500 mL. To achieve a dose of 1 mg/kg/hr, the infusion rate is 25 mL/hr; for a dose of 3 mg/kg/hr, the infusion rate is 75 mL/hr; for a dose of 5 mg/kg/hr, the infusion rate is 125 mL/hr; and for a dose of 7 mg/kg/hr, the infusion rate is 175 mL/hr.For patients weighing 100.1—120 kg: The total infusion volume = 600 mL. To achieve a dose of 1 mg/kg/hr, the infusion rate is 30 mL/hr; for a dose of 3 mg/kg/hr, the infusion rate is 90 mL/hr; for a dose of 5 mg/kg/hr, the infusion rate is 150 mL/hr; and for a dose of 7 mg/kg/hr, the infusion rate is 210 mL/hr.For patients weighing 120.1—140 kg: The total infusion volume = 700 mL. To achieve a dose of 1 mg/kg/hr, the infusion rate is 35 mL/hr; for a dose of 3 mg/kg/hr, the infusion rate is 105 mL/hr; for a dose of 5 mg/kg/hr, the infusion rate is 175 mL/hr; and for a dose of 7 mg/kg/hr, the infusion rate is 245 mL/hr.For patients weighing 140.1—160 kg: The total infusion volume = 800 mL. To achieve a dose of 1 mg/kg/hr, the infusion rate is 40 mL/hr; for a dose of 3 mg/kg/hr, the infusion rate is 120 mL/hr; for a dose of 5 mg/kg/hr, the infusion rate is 200 mL/hr; and for a dose of 7 mg/kg/hr, the infusion rate is 280 mL/hr.For patients weighing 160.1—180 kg: The total infusion volume = 900 mL. To achieve a dose of 1 mg/kg/hr, the infusion rate is 45 mL/hr; for a dose of 3 mg/kg/hr, the infusion rate is 135 mL/hr; for a dose of 5 mg/kg/hr, the infusion rate is 225 mL/hr; and for a dose of 7 mg/kg/hr, the infusion rate is 315 mL/hr.For patients weighing 180.1—200 kg: The total infusion volume = 1000 mL. To achieve a dose of 1 mg/kg/hr, the infusion rate is 50 mL/hr; for a dose of 3 mg/kg/hr, the infusion rate is 150 mL/hr; for a dose of 5 mg/kg/hr, the infusion rate is 250 mL/hr; and for a dose of 7 mg/kg/hr, the infusion rate is 350 mL/hr.
Lumizyme :- Diluted product if not used immediately can be stored at 36 to 46 degrees F for up to 24 hours- Discard product if it contains particulate matter, is cloudy, or discolored- Discard unused portion. Do not store for later use.- Do not freeze- Protect from light- Refrigerate (between 36 and 46 degrees F)Myozyme:- Protect from freezing- Protect from light- Reconstituted product should be refrigerated and used within 24 hours if not used immediately- Store unreconstituted product in refrigerator (36 to 46 degrees F)
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. 
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.
bradycardia / Rapid / 21.0-21.0anaphylactic shock / Rapid / 1.0-7.0cardiac arrest / Early / 1.0-1.0angioedema / Rapid / Incidence not knownapnea / Delayed / Incidence not knownserious hypersensitivity reactions or anaphylaxis / Rapid / Incidence not knownbronchospasm / Rapid / Incidence not knownventricular tachycardia / Early / Incidence not knownventricular fibrillation / Early / Incidence not knownheart failure / Delayed / Incidence not knownrespiratory arrest / Rapid / Incidence not knownglomerulonephritis / Delayed / Incidence not knownnephrotic syndrome / Delayed / Incidence not knownskin necrosis / Early / Incidence not known
antibody formation / Delayed / 89.0-99.0anemia / Delayed / 31.0-31.0candidiasis / Delayed / 31.0-31.0sinus tachycardia / Rapid / 8.0-23.0constipation / Delayed / 23.0-23.0chest pain (unspecified) / Early / 6.0-7.0peripheral edema / Delayed / 3.0-3.0edema / Delayed / Incidence not knowndyspnea / Early / Incidence not knownhypotension / Rapid / Incidence not knownhypoxia / Early / Incidence not knownsupraventricular tachycardia (SVT) / Early / Incidence not knownproteinuria / Delayed / Incidence not knownskin ulcer / Delayed / Incidence not known
diarrhea / Early / 0-62.0diaper dermatitis / Delayed / 36.0-36.0pharyngitis / Delayed / 9.0-36.0rhinorrhea / Early / 28.0-28.0gastroesophageal reflux / Delayed / 26.0-26.0urticaria / Rapid / 8.0-21.0abdominal pain / Early / 15.0-15.0malaise / Early / 6.0-6.0rhinitis / Early / 6.0-6.0maculopapular rash / Early / Incidence not knowninfection / Delayed / Incidence not knownarthropathy / Delayed / Incidence not known
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.
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. Systemic exposure of Myozyme is approximately dose-proportional at the doses studied (20 or 40 mg/kg/dose IV). For the 20 mg/kg/dose, mean Cmax concentration is 162 +/- 31 mcg/mL; the median Vd is 96 +/- 16 mL/kg, and the median half-life is 2.3 +/- 0.4 hours. For Lumizyme, the pharmacokinetic parameters were not-time dependent for patients who did not develop high antibody titer/inhibitory antibody. Parameter values did not change across visits at weeks 0, 12, and 52. At week 52 after bi-weekly administration, the estimate of AUC was 2700 mcg x h/ml with 30.4% coefficient of variation (CV), of Cmax was 372 mcg/ml with 22.7% CV, and of clearance was 601 mL/h with 28.2% CV. The declining portion of the concentration-time profile of alglucosidase alfa appears biphasic within the observed sampling time. The half-life for the first phase is 2.4 hours with a between subject variation of 10%; the half-life of the second phase was not determined, as concentrations of alglucosidase alfa were not sampled long enough.