avalglucosidase alfa (Rx)

>10%

Hypersensitivity reactions (48%)

Infusion-related reactions (34%)

Headache (22%)

Fatigue (18%)

Diarrhea (12%)

Nausea (12%)

Antidrug antibodies (ADAs)

• ADA cross-reactivity studies showed that antibodies to avalglucosidase alfa-ngpt were cross-reactive to alglucosidase alfa

• Treatment-naïve

  • ADA baseline (3%)
  • ADA after treatment (95%)
  • Neutralizing antibody (NAb) inhibition of enzyme activity (28%)
  • NAb inhibition of enzyme cellular uptake (39%)

• Treatment-experienced

  • ADA baseline (10-74%)
  • ADAs after treatment (17-55%)
  • NAb inhibition of enzyme activity (18%)
  • NAb inhibition of enzyme cellular uptake (10-21%)

1-10%

Arthralgia (10%)

Dizziness (10%)

Myalgia (10%)

Pruritus (8%)

Vomiting (8%)

Dyspnea (6%)

Erythema (6%)

Paresthesia (6%)

Urticaria (6%)

Hypersensitivity reactions, severe (4%)

Anaphylaxis (2%)

Contraindications

None

Cautions

Also see Black Box Warnings and Dosage Modifications

Risk of acute cardiorespiratory failure reported in patients susceptible to fluid overload and those with acute underlying respiratory illness or compromised cardiac/respiratory function; monitor vital signs more frequently

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 www.registrynxt.com or call 1-800-745-4447, extension 15500

Hypersensitivity reactions

• Severe hypersensitivity reaction (eg, anaphylaxis) reported; prior to administration, consider pretreating with antihistamines, antipyretics, and/or corticosteroids; if this occurs, discontinue immediately and administer appropriate medical treatment; may consider desensitization
• Symptoms of severe hypersensitivity reactions (eg, anaphylaxis) have included chest discomfort, erythema, generalized edema, hypotension, hypoxia, rash, respiratory distress, tongue edema, and urticaria

Infusion-associated reactions (IARs)

• IARs reported; immediate discontinuation required if severe; if mild or moderate IAR occurs, consider temporarily holding infusion or slowing infusion rate; antihistamines, antipyretics, and/or corticosteroids may be administered before infusion to reduce risk
• Some patients have been rechallenged using slower infusion rates at a dose lower than recommended dose; if the decision is made to readminister therapy, ensure patient tolerates infusion; once a patient tolerates infusion, the dose may be increased to reach recommended approved dose

Pregnancy

Data are insufficient to evaluate 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 females have not identified drug-associated risk of adverse pregnancy outcomes

Pregnant females exposed, or their healthcare providers, should report exposure by calling 1-800-745-4447, extension 15500

Clinical considerations

• Untreated Pompe disease may result in worsening respiratory and musculoskeletal symptoms in pregnant females

Animal studies

• Embryofetal toxicity studies performed in pregnant mice resulted in maternal toxicity related to immunologic response (including anaphylactoid response) and embryofetal loss at 17 times the human steady-state AUC at the recommended biweekly dose of 20 mg/kg for patients weighing ≥30 kg or 10 times the human steady-state AUC at the recommended biweekly dose of 40 mg/kg for lat-onset Pompe disease 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 fetuses at exposure up to 91 times the human steady-state AUC at recommended biweekly dosage of 20 mg/kg for patients weighing ≥30 kg or 50 times human steady-state AUC at the recommended biweekly dose of 40 mg/kg for weight <30 kg

Lactation

Data are unavailable regarding presence in human or animal milk, effects on breastfed infants, or effects on milk production

Available published literature suggests the presence of alglucosidase alfa (another hydrolytic lysosomal glycogen-specific enzyme replacement therapy) in human milk

Developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for therapy and any potential adverse effects on the breastfed infant from therapy or from underlying maternal condition

Lactating women exposed, or their healthcare providers, should report exposure by calling 1-800-633-1610, option 1

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Recombinant acid alpha-glucosidase (GAA)

Carbohydrate groups on GAA molecule bind to mannose-6-phosphate receptors, then GAA is transported into cell where it undergoes proteolytic cleavage resulting in increased enzymatic glycogen cleavage

Alpha-glucosidase is essential for normal muscle development and function; it binds to mannose-6-phosphate receptors and then is transported into lysosomes and undergoes proteolytic cleavage that results in increased enzymatic activity and ability to cleave glycogen

Absorption

Peak plasma concentration ≥30 kg: 259 mcg/mL (week 1); 242 mcg/mL (week 2)

AUC ≥30 kg: 1290 mcgh/mL (week 1); 1250 mcgh/mL (week 49)

Distribution

Vd: 3.4 L

Metabolism

Not characterized; the protein portion of avalglucosidase alfa-ngpt is expected to be metabolized into small peptides and amino acids via catabolic pathways

Elimination

Half-life: 1.6 hr

Clearance: 0.9 L/hr

IV Incompatibilities

Do not infuse in same IV line with other products

IV Compatibilities

D5W

IV Preparation

Reconstitution

• Remove required number of vials for calculated dose from refrigerator and set aside for ~30 minutes to allow them to reach room temperature
• Reconstitute each vial with 10 mL of sterile water for injection by a slow drop-wise addition down the inside of vial and not directly onto the lyophilized powder
• Do NOT invert, swirl, or shake vials; tilt and roll each vial gently; avoid forceful impact of the diluent on the lyophilized powder and avoid foaming
• Allow solution to become dissolved; after reconstitution, each vial will yield 100 mg/10 mL (10 mg/mL)
• Dilute reconstituted solution without delay; refrigerate if immediate use is not possible

Dilution

• Slowly withdraw dosage volume of reconstituted solution from each vial
• Add reconstituted solution slowly and directly into D5W for recommended total infusion volume based on the patient’s weight (see below)
• Avoid foaming, agitation of infusion bag
• Avoid air introduction into infusion bag
• Discard any unused reconstituted solution remaining in vial
• Mix infusion bag contents by gently inverting or massaging infusion bag; do NOT shake
• After dilution, final concentration of solution is 0.5-4 mg/mL
• Administer diluted solution without delay
• Recommended infusion duration is 4-7 hr
• Discard unused diluted solution after 9 hr

• Total infusion volume (20 mg/kg dose)

  • 30-34.9 kg: 200 mL
  • 35-49.9 kg: 250 mL
  • 50-59.9 kg: 300 mL
  • 60-99.9 kg: 500 mL
  • 100-119.9 kg: 600 mL
  • 120-140 kg: 700 mL

• Total infusion volume (40 mg/kg dose)

  • 5-9.9 kg: 100 mL
  • 10-19.9 kg: 200 mL
  • 20-29.9 kg: 300 mL

IV Administration

Use of in-line, low-protein–binding, 0.2-micron filter recommended for infusion

Administer infusion incrementally, as determined by the patient’s response and comfort

Consider pretreating with antihistamines, antipyretics, and/or corticosteroids

Flush IV line with D5W after infusion complete

Discard any unused diluted product after 9 hr

20 mg/kg dose infusion rate

• Initial and subsequent infusions

  • 1 mg/kg/hr IV; if no signs of infusion-associated reactions (IARs), gradually increase infusion rate q30min to 3 mg/kg/hr, 5 mg/kg/hr, and then 7 mg/kg/hr
  • Maintain infusion rate at 7 mg/kg/hr until infusion completed
  • Total infusion duration ~4-5 hr

40 mg/kg dose infusion rate

• Initial infusion

  • 1 mg/kg/hr IV; if no signs of infusion-associated reactions (IARs), gradually increase infusion rate q30min to 3 mg/kg/hr, 5 mg/kg/hr, and then 7 mg/kg/hr
  • Maintain infusion rate at 7 mg/kg/hr until infusion completed
  • Total infusion duration ~7 hr

• Subsequent infusions

  • 1 mg/kg/hr IV; if no signs of IARs, gradually increase infusion rate q30min to 3 mg/kg/hr, 5-6 mg/kg/hr, 7-8 mg/kg/hr, and optionally up to 10 mg/kg hr
  • Maintain infusion rate at highest tolerated rate until infusion completed
  • Total infusion duration ~7 hr (4 steps) or ~5 hr (5 steps)

Missed dose

• ≥1 missed dose(s): Restart treatment as soon as possible, maintaining the 2 week interval between infusions thereafter

After desensitzation

• Desensitization may be considered for hypersensitivity reactions
• If decision is made to readminister therapy, ensure patient tolerates infusion; if tolerated, may increase dose and/or rate to reach approved recommended dosage;
• If mild or moderate hypersensitivity reaction occurs, infusion rate may be slowed or temporarily stopped

Storage

Unopened vials

• Refrigerate at 2-8ºC (36-46ºF)
• Do not use after expiration date on vial

Reconstituted or diluted solution

• Refrigerate at 2-8ºC (36-46ºF) for up to 24 hr
• Do not freeze

• Diluted solution

  • Completely infuse diluted solution within 9 hr after removal from refrigerator
  • If removed from refrigerator, it must not be re-stored in the refrigerator