pegunigalsidase alfa (Rx)

>10%

Infusion-associated reaction (32%)

Nasopharyngitis (21%)

Headache (21%)

Diarrhea (19%)

Fatigue (17%)

Nausea (17%)

Back pain (15%)

Pain in extremity (15%)

Sinusitis (15%)

Abdominal pain (12%)

Proteinuria (12%)

1-10%

Hypersensitivity (9%)

Upper respiratory tract congestion (8%)

Neuralgia (8%)

Peripheral neuropathy (6%)

Sciatica (6%)

Infusion site extravasation (6%)

Hematuria (6%)

Frequency Not Defined

Membranoproliferative glomerulonephritis in 1 patient

Contraindications

None

Cautions

Hypersensitivity

• Hypersensitivity reactions, including anaphylaxis, reported
• Consider pretreating with antihistamines, antipyretics, and/or corticosteroids
• Risk of hypersensitivity may be increased in certain patients with pre-existing anti-drug antibodies (ADA) from prior ERT; consider monitoring patients who demonstrate hypersensitivity reactions during treatment for presence of IgG and IgE ADA
• Also, see Boxed Warning and Dosage Modifications

Infusion-associated reactions (IARs)

• IARs reported, including nausea, chills, pruritus, rash, chest pain, dizziness, vomiting, asthenia, pain, sneezing, dyspnea, nasal congestion, throat irritation, abdominal pain, erythema, diarrhea, burning sensation, neuralgia, headache, paresthesia, tremor, agitation, increased body temperature, flushing, bradycardia, myalgia, hypertension, and hypotension
• Reactions may occur up to 24 hr after completing infusion
• Consider pretreating with antihistamines, antipyretics, and/or corticosteroids
• Risk of hypersensitivity may be increased in certain patients with pre-existing anti-drug antibodies (ADA) from prior ERT; consider monitoring
• Patients with advanced Fabry disease may have compromised cardiac function which, may predispose them to higher risk of severe complications from IARs; closely monitor patients with compromised cardiac function if administered to these patients
• Also, see Dosage Modifications

Membranoproliferative glomerulonephritis

• A case of membranoproliferative glomerulonephritis with immune depositions in the kidney was reported during clinical trials
• This event led to a decline in renal function that slowly improved upon discontinuation but did not return to baseline by the end of the clinical trial
• Monitor serum creatinine and urinary protein to creatinine ratio
• If glomerulonephritis is suspected, discontinue pegunigalsidase alfa until a diagnostic evaluation can be conducted

Pregnancy

There are no available data regarding use in pregnant females to evaluate a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes

As an enzyme replacement, pegunigalsidase alfa is not expected to cause adverse outcomes during pregnancy

Pregnancy safety study

• There is a pregnancy safety study for pegunigalsidase alfa
• If a patient becomes pregnant during treatment, report exposure by calling 1-888-661-9260 or visiting chiesirarediseases.com/contact-us/medical-information-form

Animal studies

• No adverse effects on embryofetal development were observed in pregnant rats administered pegunigalsidase alfa IV twice per week at exposures up to 3.6 times the maximum recommended human dose (MRHD)
• Maternal toxicity was observed in pregnant rabbits administered pegunigalsidase alfa IV twice per week at doses that were ≥3.2 times the MRHD (based on human equivalent dose)

Lactation

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

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

Fabry disease is caused by deficiency of the lysosomal enzyme alpha-galactosidase A involved in the metabolism of globotriaosylceramide (GL-3)

Pegunigalsidase alfa is an exogenous source of alpha-galactosidase A

Pegunigalsidase alfa is internalized and transported into lysosomes where it is thought to exert enzymatic activity and reduce accumulated Gb3 and reduce GL-3 deposition in capillary endothelium, and thereby, improving associated clinical manifestations (eg, vascular occlusion, stroke, renal failure, heart failure)

Absorption

Peak plasma concentration

• Day 1: 11.1 mcg/mL
• Week 13: 11.9 mcg/mL
• Week 26: 13.3 mcg/mL
• Week 52: 17.3 mcg/mL

AUC

• Day 1: 391 mcgh/mL
• Week 13: 510 mcgh/mL
• Week 26: 748 mcgh/mL
• Week 52: 1428 mcgh/mL

Distribution

Vd

• Day 1: 321 mL/kg
• Week 13: 271 mL/kg
• Week 26: 226 mL/kg
• Week 52: 186 mL/kg

Metabolism

Expected metabolism into small peptides by catabolic pathways

Elimination

Half-life

• Day 1: 78.9 hr
• Week 13: 85.7 hr
• Week 26: 96.5 hr
• Week 52: 121 hr

Clearance

• Day 1: 2.9 mL/hr/kg
• Week 13: 2.3 mL/hr/kg
• Week 26: 1.6 mL/hr/kg
• Week 52: 1.1 mL/hr/kg

IV Compatibilities

0.9% NaCl

IV Preparation

Determine number of pegunigalsidase alfa vials to be diluted based on actual body weight in kg and the recommended dose

Round number of vials up to next whole number

Remove vials from refrigerator and allow to sit for 15-30 minutes at room temperature before use; do not use an external heat source to heat product (heat may damage product)

Visually inspect solution for particulate matter and discoloration

Solution should be clear and colorless; discard vial(s) if solution discolored or if visible particulate matter is present

Further dilution required

• Dilute solution required for dose in 0.9% NaCl to a total volume based on actual body weight

• Total volume of dilution and body weight

  • <70 kg: 150 mL
  • 70-100 kg: 250 mL
  • >100 kg: 500 mL
• Before adding volume of pegunigalsidase alfa dose, remove equal volume of 0.9% NaCl from infusion bag
• Withdraw dose from vials and inject solution directly into 0.9% NaCl through infusion bag port; do not inject in the airspace within the infusion bag
• Discard any unused solution remaining in vial(s)
• Gently invert infusion bag to mix; avoid vigorous shaking or agitation

IV Administration

Administer pretreatment regimen if applicable

Appropriate medical support measures including cardiopulmonary resuscitation equipment should be readily available during administration

Use an in-line low protein-binding, 0.2 micron, in-line filter

At end of infusion, flush line with 0.9% NaCl using same infusion rate at completion of infusion

Do not infuse in same IV line with other products

If initial 4-6 infusions tolerated, duration of every third infusion may be decreased in decrements of 30 minutes as tolerated; minimum recommended infusion duration is 1.5 hr

Infusion rate for initial 4-6 doses

• Base infusion rate on actual body weight

• Enzyme replacement therapy (ERT)-experienced patients

  • <70 kg: 150 mL total infusion volume at 0.83 mL/min (50 mL/hr)
  • 70-100 kg: 250 mL total infusion volume at 1.39 mL/min (83 mL/hr)
  • >100 kg: 500 mL total infusion volume at 2.78 mL/min 167 mL/hr)

• Enzyme replacement therapy (ERT)-naïve patients

  • <70 kg: 150 mL total infusion volume at 0.63 mL/min (37.5 mL/hr)
  • 70-100 kg: 250 mL total infusion volume at 1 mL/min (60 mL/hr)
  • >100 kg: 500 mL total infusion volume at 1.38 mL/min (83 mL/hr)

• Previously treated with an ERT with infusion over 3 hours

  • Use the same infusion rate for pegunigalsidase alfa infusion
  • May decrease duration of every third infusion after the initial 4-6 infusions in decrements of 30 minutes as tolerated; minimum recommended infusion duration is 1.5 hr

Missed dose

• If ≥1 doses missed, restart treatment as soon as possible, maintaining the 2-week interval between infusions thereafter
• Do not double a dose to compensate for missed dose

Home infusion

• May consider for patients who have reached an infusion duration that is tolerated well
• Decision to move to home infusion based on evaluation and recommendation by a healthcare provider
• Infusion duration should remain constant for home administration and duration should only be decreased in a healthcare facility
• Contact clinician if dose is missed dose or delayed

Storage

Unopened vials

• Refrigerate at 2-8ºC (36-46ºF)
• Do not freeze
• Do not shake

Diluted solution

• Refrigerate at 2-8ºC (36-46ºF) for up to 24 hr, OR
• Store at room temperature of 20-25ºC (68-77ºF) for up to 8 hr
• Solution must be infused within 8 hr after removal from refrigerator or if stored at room temperature, inclusive of total infusion time, or discarded
• Do not freeze
• Do not shake