cipaglucosidase alfa (Rx)

>10%

Infusion-associated reactions (32%)

Hypersensitivity reactions (27%)

1-10%

Headache (8.2%)

Diarrhea (5.9%)

Dizziness (4.7%)

Dyspnea (3.5%)

Abdominal distention (3.5%)

Pyrexia (3.5%)

Rash (3.5%)

Severe infusion-associated reactions (3%)

Severe hypersensitivity reactions (3%)

Abdominal pain (2.4%)

Nausea (2.4%)

Chills (2.4%)

Dysgeusia (2.4%)

Flushing (2.4%)

Muscle spasms (2.4%)

Pruritus (2.4%)

Tachycardia (2.4%)

Urticaria (2.4%)

Contraindications

Pregnancy

Cautions

Hypersensitivity reactions

• Hypersensitivity reactions, including anaphylaxis, reported; ensure appropriate medical support measures are readily available, including cardiopulmonary resuscitation equipment
• Anaphylaxis signs and symptoms included dyspnea, rash, hypotension, bronchospasm, edema, pharyngeal edema, and tongue swelling
• Symptoms of severe hypersensitivity reactions included urticaria, pruritus, and flushing
• See dosage and administration modifications for recommendations to discontinue, slow rate, or need of premedication

• Readministering/desensitization

  • Consider risks and benefits of readministering therapy following severe hypersensitivity reaction (including anaphylaxis)
  • Patients may be rechallenged using slower infusion rates
  • In patients with severe hypersensitivity reaction, desensitization measures to this drug may be considered
  • If readministered, ensure patient tolerates the infusion
  • If infusion tolerated, dose and/or rate may be increased to reach approved recommended dosage

Infusion-associated reactions

• Antihistamines, antipyretics, and/or corticosteroids can be given before administration to reduce risk of IARs, however, IARs may still occur after receiving pretreatment
• Ensure appropriate medical support measures are readily available, including cardiopulmonary resuscitation equipment
• Discontinue infusion immediately if severe reaction occurs; may attempt slower infusion rate if tolerated
• If mild or moderate IARs occur regardless of pretreatment, decreasing infusion rate or temporarily stopping infusion may ameliorate symptoms
• Assess benefits and risks of readministering therapy following severe IARs; may rechallenge using slower infusion rate; once infusion rate tolerated, may increase to reach recommended infusion rate

Cardiorespiratory failure

• 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 infusion
• Perform more frequent monitoring of vitals
• Some patients may require prolonged observation times

Embryofetal toxicity

• Contraindicated during pregnancy
• Based on findings from animal reproduction studies, cipaglucosidase alfa plus miglustat may cause embryofetal harm when administered to pregnant females
• Verify pregnancy status in females of reproductive potential before initiating

Pregnancy

Contraindicated during pregnancy

Based on findings from animal reproduction studies, may cause embryofetal harm when administered to pregnant females

Verify the pregnancy status in females of reproductive potential before initiating

Animal studies

• In a rabbit embryofetal development study, great vessel and cardiac malformations were increased in offspring of pregnant rabbits treated with cipaglucosidase alfa in combination with miglustat at 16-fold and 3-fold, respectively, the maximum recommended human dose (MRHD) based on plasma AUC exposure
• A No Observed Adverse Effect Level (NOAEL) was not identified for the combination

Contraception

• Advise females of reproductive potential to use effective contraception during treatment and for at least 60 days after last dose

Infertility

• Females: Based on preimplantation loss observed in female rats, may impair human female fertility; unknown whether this preimplantation loss in female rats would be sustained if dosing were discontinued before mating
• Males: Based on reversible increases in preimplantation loss in male rats, may impair human male fertility

Lactation

Data are not available regarding presence of cipaglucosidase alfa, alone or in combination with miglustat, in human milk, effects on breastfed infants, or effects on milk production

Cipaglucosidase alfa is present in animal milk; when a drug is present in animal milk, it is likely that it will be present in human milk

Based on findings in animal studies, the use of cipaglucosidase alfa in combination with miglutstat may lead to serious adverse reactions in breastfed infants

Advise females that breastfeeding is not recommended during treatment

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

Pompe disease (glycogen storage disease type II, acid maltase deficiency, and glycogenosis type II) is an inherited disorder of glycogen metabolism caused by a deficiency of lysosomal acid alpha-glucosidase (GAA) that degrades glycogen to glucose in the lysosome

Cipaglucosidase alfa is an enzyme replacement therapy; recombinant human acid alpha-glucosidase enzyme with optimized carbohydrate structures to enhance uptake into muscle cells

Used with miglustat, which binds with, stabilizes, and reduces inactivation of cipaglucosidase alfa in blood

Absorption

Peak plasma concentration

• With miglustat: 345 mcg/mL
• Without miglustat: 325 mcg/mL

AUC

• With miglustat: 1,812 mcg⋅h/mL
• Without miglustat: 1,410 mcg⋅h/mL

Distribution

Vd: 2-4.7 L

Metabolism

Not characterized, but is expected to be metabolized into small peptides and amino acid via catabolic pathways

Elimination

Half-life: 2.1 hr

Total body clearance: 0.8 L/hr

IV Compatibilities

0.9% NaCl

IV Preparation

Use aseptic technique during preparation to reconstitute and dilute cipaglucosidase alfa

Reconstitution

• Determine the number of vials to be reconstituted based on calculated dose
• Remove vials from refrigerator and set aside ~30 minutes to come to room temperature
• Slowly inject 7.2 mL of sterile water for injection down inside wall of each vial to avoid foaming; avoid forceful impact of sterile water on lyophilized powder
• Roll and tilt each vial to allow lyophilized powder to dissolve completely (typically takes 2 minutes)
• Reconstituted vial will yield concentration of 15 mg/mL
• Do not invert, swirl, or shake vial
• Visually inspect for particulate matter and discoloration; solution should appear clear to opalescent, colorless to yellowish, and essentially particle free
• Discard if foreign matter observed or solution is discolored

Dilution

• Remove airspace within a bag of 0.9% NaCl
• Remove an equal volume of 0.9% NaCl from bag that will be replaced by the total volume (mL) of reconstituted drug
• Slowly withdraw 7 mL (105 mg) of reconstituted solution from each vial dose obtained
• Discard any remaining reconstituted solution in last vial
• Add reconstituted solution slowly and directly into infusion bag
• To prevent foaming, gently invert infusion bag to mix solution and avoid vigorous shaking or agitation
• After dilution, solution will have a final concentration of 0.5-4 mg/mL of cipaglucosidase alfa
• Do not use pneumatic tube to transport the infusion bag
• Administer diluted solution at room temperature without delay (or store as described below)

Before administration

• Inspect infusion bag for foaming; if present, let foam dissipate before administering
• If diluted solution was refrigerated, allow solution to equilibrate to room temperature for 30 minutes before infusing

IV Administration

Use an administration set with an inline low protein binding 0.2-micron filter; change filter if it becomes blocked

Administer by IV infusion over ~4 hr

Initiate ~1 hr after miglustat oral dose

Do not infuse in same IV line with other products

IV infusion rate

• Initial recommended infusion rate iw 1 mg/kg/hr
• Gradually increase rate by 2 mg/kg/hr q30 minutes if there are no signs of hypersensitivity or infusion-associated reactions (IARs) until maximum rate of 7 mg/kg/hr
• Step 1: 1 mg/kg/hr initially
• Step 2: After 30 minutes, increase to 3 mg/kg/hr
• Step 3: After 30 minutes, increase to 5 mg/kg/hr
• Step 4: After 30 minutes, maintain rate at 7 mg/kg/hr until infusion has been completed, unless reaction occurs that necessitates interruption, rate reduction, or discontinuation

Recommended infusion bag volume by patient weight

• 40-50 kg: 250 mL
• 50.1-60 kg: 300 mL
• 60.1-100 kg: 500 mL
• 100.1-120 kg: 600 mL
• 120.1-140 kg: 700 mL

Missed dose

• If cipaglucosidase alfa infusion cannot be started within 3 hr of oral administration of miglustat, reschedule administration at least 24 hr after miglustat was last taken
• If miglustat in combination with cipaglucosidase alfa are both missed, restart treatment as soon as possible

Storage

Unopened vials

• Refrigerate at 2-8ºC (36-46ºF) in original carton to protect from light
• Do not freeze

Reconstituted solution

• If not used immediately, refrigerate at 2-8ºC (36-46ºF) for up to 24 hr
• Do not freeze

Diluted solution

• If not used immediately, refrigerate at 2-8ºC (36-46ºF) for up to 16 hr
• Storage at room temperature not recommended
• Do not freeze

• After removal from refrigerator

  • Completely infuse within 6 hr
  • Do not restore in refrigerator
  • Discard if refrigerated >16 hr or if diluted solution is not able to be completely infused within 6 hr after removal from the refrigerator