Avalglucosidase Alfa (Monograph)

Brand name: Nexviazyme
Drug class: Enzymes

Medically reviewed by Drugs.com on Aug 21, 2023. Written by ASHP.

Introduction

Avalglucosidase alfa-ngpt is a hydrolytic lysosomal glycogen-specific enzyme.

Uses for Avalglucosidase Alfa

Avalglucosidase alfa-ngpt has the following uses:

Avalglucosidase alfa-ngpt is a hydrolytic lysosomal glycogen-specific enzyme indicated for the treatment of patients 1 year of age and older with late-onset Pompe disease (lysosomal acid alpha-glucosidase [GAA] deficiency).

Avalglucosidase Alfa Dosage and Administration

General

Avalglucosidase alfa-ngpt is available in the following dosage form(s) and strength(s):

For injection: 100 mg of avalglucosidase alfa-ngpt as a lyophilized powder in a single-dose vial for reconstitution.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

• Consider administering antihistamines, antipyretics, and/or corticosteroids prior to avalglucosidase alfa-ngpt administration to reduce the risk of infusion-associated reactions (IARs).

• Must be reconstituted and diluted prior to use.

• Administer by intravenous infusion.

• See full prescribing information for administration instructions, including the recommended infusion rate schedule.

Pediatric Patients

Dosage and Administration

For pediatric patients ≥1 year of age weighing ≥30 kg, the recommended dosage is 20 mg/kg (of actual body weight) every two weeks.

For pediatric patients ≥1 year of age weighing <30 kg, the recommended dosage is 40 mg/kg (of actual body weight) every two weeks.

See the full prescribing information for dosage modifications due to hypersensitivity reactions or IARs.

Adults

Dosage and Administration

For patients weighing ≥30 kg, the recommended dosage is 20 mg/kg (of actual body weight) every two weeks.

For patients weighing <30 kg, the recommended dosage is 40 mg/kg (of actual body weight) every two weeks.

See the full prescribing information for dosage modifications due to hypersensitivity reactions or IARs.

Cautions for Avalglucosidase Alfa

Contraindications

None.

Warnings/Precautions

Hypersensitivity Reactions Including Anaphylaxis

Prior to avalglucosidase alfa-ngpt administration, consider pretreating with antihistamines, antipyretics, and/or corticosteroids. Appropriate medical support measures, including cardiopulmonary resuscitation equipment, should be readily available during avalglucosidase alfa-ngpt administration.

If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, avalglucosidase alfa-ngpt should be discontinued immediately and appropriate medical treatment should be initiated. The risks and benefits of readministering avalglucosidase alfa-ngpt following severe hypersensitivity reaction (including anaphylaxis) should be considered. Some patients have been rechallenged using slower infusion rates at a dosage lower than the recommended dosage. In patients with severe hypersensitivity reaction, a desensitization procedure to avalglucosidase alfa-ngpt may be considered. If the decision is made to readminister avalglucosidase alfa-ngpt, ensure the patient tolerates the infusion. If the patient tolerates the infusion, the dosage (dose and/or the rate) may be increased to reach the approved recommended dosage.

If a mild or moderate hypersensitivity reaction occurs, the infusion rate may be slowed or temporarily stopped.

Life-threatening hypersensitivity reactions, including anaphylaxis, have been reported in avalglucosidase alfa-ngpt-treated patients. In clinical studies, 67 (48%) avalglucosidase alfa-ngpt-treated patients experienced hypersensitivity reactions, including 6 (4%) patients who reported severe hypersensitivity reactions and 3 (2%) additional patients who experienced anaphylaxis; 1 patient experiencing anaphylaxis discontinued from the study. Some of the hypersensitivity reactions were IgE mediated. Anaphylaxis signs and symptoms included respiratory distress, chest discomfort, flushing, cough, erythema, lip swelling, pruritus, swollen tongue, dysphagia, and rash. Symptoms of severe hypersensitivity reactions included respiratory distress, erythema, urticaria, tongue edema, and rash. Increased incidence of hypersensitivity reactions was observed in patients with higher antidrug antibody (ADA) titers.

Infusion-associated Reactions

Antihistamines, antipyretics, and/or corticosteroids can be given prior to avalglucosidase alfa-ngpt administration to reduce the risk of infusion-associated reactions (IARs). However, IARs may still occur in patients after receiving pretreatment.

If severe IARs occur, consider immediate discontinuation of avalglucosidase alfa-ngpt, initiation of appropriate medical treatment, and the benefits and risks of readministering avalglucosidase alfa-ngpt following severe IARs. Some patients have been rechallenged using slower infusion rates at a dose lower than the recommended dose. Once a patient tolerates the infusion, the dose may be increased to reach the recommended approved dose.

If mild or moderate IARs occur regardless of pretreatment, decreasing the infusion rate or temporarily stopping the infusion may ameliorate the symptoms.

In clinical studies, IARs were reported to occur at any time during and/or within a few hours after the avalglucosidase alfa-ngpt infusion and were more likely to occur with higher infusion rates. IARs were reported in 48 (34%) avalglucosidase alfa-ngpt-treated patients in clinical studies. In these studies, 5 (4%) avalglucosidase alfa-ngpt-treated patients reported 10 severe IARs including symptoms of chest discomfort, nausea, dysphagia, erythema, respiratory distress, tongue edema, urticaria, and increased blood pressure. The majority of IARs were assessed as mild to moderate. IARs that led to treatment discontinuation were chest discomfort, cough, dizziness, erythema, flushing, nausea, ocular hyperemia, and respiratory distress. Increased incidence of IARs was observed in patients with higher ADA titers.

Patients with an acute underlying illness at the time of avalglucosidase alfa-ngpt infusion appear to be at greater risk for IARs. Patients with advanced Pompe disease may have compromised cardiac and respiratory function, which may predispose them to a higher risk of severe complications from IARs.

Risk of Acute Cardiorespiratory Failure in Susceptible Patients

Patients susceptible to fluid volume overload, or those with acute underlying respiratory illness or compromised cardiac or respiratory function for whom fluid restriction is indicated may be at risk of serious exacerbation of their cardiac or respiratory status during the avalglucosidase alfa-ngpt infusion. More frequent monitoring of vitals should be performed during avalglucosidase alfa-ngpt infusion in these patients. Some patients may require prolonged observation times.

Specific Populations

Pregnancy

Risk Summary: Available data from case reports of avalglucosidase alfa-ngpt use in pregnant women are insufficient to evaluate for a drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. However, available data from postmarketing reports and published case reports on alglucosidase alfa (another hydrolytic lysosomal glycogen-specific enzyme replacement therapy) use in pregnant women have not identified a drug-associated risk of adverse pregnancy 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.

Embryofetal toxicity studies performed in pregnant mice resulted in maternal toxicity related to an immunologic response (including an anaphylactoid response) and embryofetal loss at 17 times the human steady-state AUC at the recommended biweekly dose of 20 mg/kg for late-onset Pompe disease (LOPD) patients weighing ≥30 kg or 10 times the human steady-state AUC at the recommended biweekly dose of 40 mg/kg for LOPD patients weighing <30 kg. Avalglucosidase alfa-ngpt did not cross the placenta in mice; therefore, the adverse effects were likely related to the immunologic response in the mothers. Embryofetal toxicity studies performed in pregnant rabbits showed no adverse effects on the fetuses at exposure up to 91 times the human steady-state AUC at the recommended biweekly dosage of 20 mg/kg for LOPD patients weighing ≥30 kg or 50 times the human steady-state AUC at the recommended biweekly dose of 40 mg/kg for LOPD patients weighing <30 kg.

Pregnant women exposed to avalglucosidase alfa-ngpt, or their healthcare providers, should report avalglucosidase alfa-ngpt exposure by calling 800-745-4447, extension 15500.

Clinical Considerations: Disease-associated maternal and/or embryo-fetal risk. Untreated Pompe disease has been associated with worsening respiratory and musculoskeletal symptoms in some pregnant women.

Animal Data: The majority of reproductive toxicity studies in mice included pretreatment with diphenhydramine (DPH) to prevent or minimize hypersensitivity reactions. The effects of avalglucosidase alfa-ngpt were evaluated based on comparison with a control group treated with DPH alone. Rabbits tested in reproductive toxicity studies were not pretreated with DPH because hypersensitivity reactions were not observed.

Embryo-fetal toxicity studies performed in pregnant mice at doses of 0, 10, 20, or 50 mg/kg/day administered intravenously once daily on gestational days 6 through 15 resulted in an immunologic response, including an anaphylactoid response, in some dams at the highest dose of 50 mg/kg/day (17 times the human steady-state AUC at the recommended biweekly dose of 20 mg/kg for LOPD patients weighing ≥30 kg or 10 times the human steady-state AUC at the recommended biweekly dose of 40 mg/kg for LOPD patients weighing <30 kg). Increased postimplantation loss and mean number of late resorptions were observed in this group. Placental transfer studies determined that avalglucosidase alfa-ngpt was not transported from the maternal to the fetal circulation in mice, suggesting that the embryofetal effects were due to maternal toxicity relating to the immunologic response. The maternal no observed adverse effect level (NOAEL) was 50 mg/kg/day intravenously (17 times the human AUC) and the developmental NOAEL was 20 mg/kg/day intravenously (4.8 times the human AUC).

Embryo-fetal toxicity studies performed in rabbits at doses of 0, 30, 60, and 100 mg/kg/day administered intravenously once daily on gestational days 6 through 19 resulted in no adverse effects in the fetuses at the highest dose (100 mg/kg/day; 91 times the human steady-state AUC at the recommended biweekly dosage of 20 mg/kg for LOPD patients weighing ≥30 kg or 50 times the human steady-state AUC at the recommended biweekly dose of 40 mg/kg for LOPD patients weighing <30 kg). Furthermore, the administration of avalglucosidase alfa-ngpt intravenously every other day in mice from gestational day 6 through postpartum day 20 did not produce adverse effects in the offspring at the highest dose of 50 mg/kg (maternal exposure not evaluated).

Lactation

Risk Summary: There are no data on the presence of avalglucosidase alfa-ngpt in human or animal milk, the effects on the breastfed infant, or the effects on milk production. Available published literature suggests the presence of alglucosidase alfa (another hydrolytic lysosomal glycogen-specific enzyme replacement therapy) in human milk.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for avalglucosidase alfa-ngpt and any potential adverse effects on the breastfed child from avalglucosidase alfa-ngpt or from the underlying maternal condition.

Lactating women exposed to avalglucosidase alfa-ngpt, or their healthcare providers, should report avalglucosidase alfa-ngpt exposure by calling 800-745-4447, extension 15500.

Pediatric Use

The safety and effectiveness of avalglucosidase alfa-ngpt for the treatment of late-onset Pompe disease (LOPD) have been established in pediatric patients 1 year of age and older. Use of avalglucosidase alfa-ngpt for this indication is supported by evidence from two clinical studies which included adults with LOPD and 1 pediatric patient with LOPD (16 years of age) and from safety experience in 19 pediatric patients with infantile-onset Pompe disease (IOPD) (1–12 years of age) treated with avalglucosidase alfa-ngpt. Avalglucosidase alfa-ngpt is not approved for the treatment of IOPD.

The safety profile of avalglucosidase alfa-ngpt in pediatric patients 1–12 years old with Pompe disease was similar to the safety profile of the drug in adults and older pediatric patients with LOPD.

The safety and effectiveness of avalglucosidase alfa-ngpt have not been established in pediatric patients younger than 1 year of age.

Geriatric Use

Clinical studies with avalglucosidase alfa-ngpt included 14 patients 65–74 years of age and 3 patients 75 years of age and older. The recommended dosage in geriatric patients is the same as the recommended dosage in younger adult patients.

Common Adverse Effects

The most common adverse reactions (>5%) were headache, fatigue, diarrhea, nausea, arthralgia, dizziness, myalgia, pruritus, vomiting, dyspnea, erythema, paresthesia, and urticaria.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Please see product labeling for drug interaction information.

Actions

Mechanism of Action

Pompe disease (also known as glycogen storage disease type II, acid maltase deficiency, and glycogenosis type II) is an inherited disorder of glycogen metabolism caused by a deficiency of the lysosomal enzyme acid α-glucosidase (GAA), which results in intralysosomal accumulation of glycogen in various tissues.

Avalglucosidase alfa-ngpt provides an exogenous source of GAA. The M6P on avalglucosidase alfa-ngpt mediates binding to M6P receptors on the cell surface with high affinity. After binding, it is internalized and transported into lysosomes where it undergoes proteolytic cleavage that results in increased GAA enzymatic activity. Avalglucosidase alfa-ngpt then exerts enzymatic activity in cleaving glycogen.

Advice to Patients

• Advise the patients and caregivers that reactions related to the infusion may occur during and after avalglucosidase alfa-ngpt treatment and may include anaphylactic reactions, other serious or severe hypersensitivity reactions, and infusion-associated reactions (IARs). Inform patients of the signs and symptoms of hypersensitivity reactions and IARs and have them seek medical care should signs and symptoms occur.

• Advise patients and caregivers that patients with underlying respiratory illness or compromised cardiac or respiratory function may be at risk of acute cardiorespiratory failure from volume overload during avalglucosidase alfa-ngpt infusion.

• Pregnant or lactating women exposed to avalglucosidase alfa-ngpt, or their healthcare providers, should report avalglucosidase alfa-ngpt exposure by calling 800-745-4447, extension 15500.

• Inform patients and their caregivers that the Pompe Registry has been established in order to better understand the variability and progression of Pompe disease, and to continue to monitor and evaluate long-term effects of avalglucosidase alfa-ngpt. Patients and their caregivers should be encouraged to participate in the Pompe Registry and advised that their participation is voluntary and may involve long-term follow-up. For more information regarding the registry program, visit [Web] or call 800-745-4447, extension 15500.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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