HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use MYOZYME safely and effectively. See full prescribing information for MYOZYME.
MYOZYME ® (alglucosidase alfa)
Injectable for intravenous infusion
Initial U.S. Approval: 2006
WARNING: ANAPHYLAXIS, SEVERE ALLERGIC AND IMMUNE MEDIATED REACTIONS and RISK OF CARDIORESPIRATORY FAILURE
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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.
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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)
INDICATIONS AND USAGE
MYOZYME® (alglucosidase alfa) is a lysosomal glycogen-specific enzyme indicated for use in patients with Pompe disease (GAA deficiency). MYOZYME has been shown to improve ventilator-free survival in patients with infantile-onset Pompe disease as compared to an untreated historical control, whereas use of MYOZYME in patients with other forms of Pompe disease has not been adequately studied to assure safety and efficacy. (1)
DOSAGE AND ADMINISTRATION
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The recommended dosage of MYOZYME is 20 mg/kg body weight administered every 2 weeks as an intravenous infusion. (2)
DOSAGE FORMS AND STRENGTHS
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Dosage form: Lyophilized powder for solution for intravenous infusion.
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Dosage strength: 5 mg/mL. (3)
CONTRAINDICATIONS
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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)
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Severe cutaneous and systemic immune mediated reactions: Monitor patients for the development of systemic immune mediated reactions involving skin and other organs. (5.2)
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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)
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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)
ADVERSE REACTIONS
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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)
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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
USE IN SPECIFIC POPULATIONS
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Pregnancy: Physicians are encouraged to enroll pregnant patients in the Pompe Registry. (8.1, 17)
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Nursing Mothers: Physicians are encouraged to enroll nursing patients in the Pompe Registry. (8.3, 17)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 5/2014
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
MYOZYME® (alglucosidase alfa) [see Description (11)] is a lysosomal glycogen-specific enzyme indicated for use in patients with Pompe disease (GAA deficiency). MYOZYME has been shown to improve ventilator-free survival in patients with infantile-onset Pompe disease as compared to an untreated historical control, whereas use of MYOZYME in patients with other forms of Pompe disease has not been adequately studied to assure safety and efficacy [see Clinical Studies (14) ].
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dose
The recommended dosage regimen of MYOZYME is 20 mg/kg body weight administered every 2 weeks as an intravenous infusion.
2.2 Instructions for Use
MYOZYME does not contain any preservatives. Vials are single-use only. Any unused product should be discarded.
The total volume of infusion is determined by the patient’s body weight and should be administered over approximately 4 hours.
Infusions should be administered in a step-wise manner using an infusion pump. The initial infusion rate should be no more than 1 mg/kg/hr. The infusion rate may be increased by 2 mg/kg/hr every 30 minutes, after patient tolerance to the infusion rate is established, until a maximum rate of 7 mg/kg/hr is reached. Vital signs should be obtained at the end of each step. If the patient is stable, MYOZYME may be administered at the maximum rate of 7 mg/kg/hr until the infusion is completed. The infusion rate may be slowed and/or temporarily stopped in the event of infusion reactions. See Table 1 below for the rate of infusion at each step, expressed as mL/hr based on the recommended infusion volume by patient weight.
Reconstitution, dilution and administration
MYOZYME should be reconstituted, diluted and administered by a healthcare professional.
Use aseptic technique during preparation. Do not use filter needles during preparation.
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Determine the number of vials to be reconstituted based on the individual patient’s weight and the recommended dose of 20 mg/kg.
Patient weight (kg) x dose (mg/kg) = patient dose (in mg)
Patient dose (in mg) divided by 50 mg/vial = number of vials to reconstitute. If the number of vials includes a fraction, round up to the next whole number.
Example: Patient weight (16 kg) x dose (20 mg/kg) = patient dose (320 mg)
320 mg divided by 50 mg/vial = 6.4 vials; therefore, 7 vials should be reconstituted
Remove the required number of vials from the refrigerator and allow them to reach room temperature prior to reconstitution (approximately 30 minutes).
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Reconstitute each MYOZYME vial by slowly injecting 10.3 mL of Sterile Water for Injection, USP to the inside wall of each vial. Each vial will yield 5 mg/mL. The total extractable dose per vial is 50 mg per 10 mL. Avoid forceful impact of the water for injection on the powder and avoid foaming. This is done by slow drop-wise addition of the water for injection down the inside of the vial and not directly onto the lyophilized cake. Tilt and roll each vial gently. Do not invert, swirl, or shake.
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The reconstituted MYOZYME solution should be protected from light.
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Perform an immediate visual inspection on the reconstituted vials for particulate matter and discoloration. If upon immediate inspection opaque particles are observed or if the solution is discolored do not use. The reconstituted solution may occasionally contain some alglucosidase alfa particles (typically less than 10 in a vial) in the form of thin white strands or translucent fibers subsequent to the initial inspection. This may also happen following dilution for infusion. These particles have been shown to contain alglucosidase alfa and may appear after the initial reconstitution step and increase over time. Studies have shown that these particles are removed via in-line filtration without having a detectable effect on the purity or strength.
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MYOZYME should be diluted in 0.9% Sodium Chloride for Injection, USP, immediately after reconstitution, to a final MYOZYME concentration of 0.5 to 4 mg/mL. See Table 1 for the recommended total infusion volume based on patient weight.
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Slowly withdraw the reconstituted solution from each vial. Avoid foaming in the syringe.
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Remove airspace from the infusion bag to minimize particle formation due to the sensitivity of MYOZYME to air-liquid interfaces.
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Add the reconstituted MYOZYME solution 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.
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Gently invert or massage the infusion bag to mix. Do not shake.
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Administer MYOZYME using an in-line low protein-binding 0.2 µm filter.
MYOZYME should not be infused in the same intravenous line with other products.
MYOZYME does not contain any preservatives. Vials are single-use only. Discard any unused product.
3 DOSAGE FORMS AND STRENGTHS
MYOZYME is supplied as a sterile, nonpyrogenic, white to off-white, lyophilized cake or powder for reconstitution with Sterile Water for Injection, USP to yield a concentration of 5 mg/mL; and then further diluted with 0.9% Sodium Chloride for Injection, USP for intravenous infusion.
Single-use vials are available in 50 mg dosage only.
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
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 eva luate 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 eva luated prior to the initiation of MYOZYME treatment and periodically thereafter.
6 ADVERSE REACTIONS
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.
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