Pegunigalsidase Alfa-iwxj (Monograph)

Brand name: Elfabrio
Drug class: Enzymes

Introduction

Pegunigalsidase alfa-iwxj, a hydrolytic lysosomal neutral glycosphingolipid-specific enzyme, is a pegylated recombinant form of human α-galactosidase A.

Uses for Pegunigalsidase Alfa-iwxj

Pegunigalsidase alfa-iwxj has the following uses:

Pegunigalsidase alfa-iwxj is indicated for the treatment of adults with confirmed Fabry disease.

Pegunigalsidase Alfa-iwxj Dosage and Administration

Administration

Pegunigalsidase alfa-iwxj is available in the following dosage form(s) and strength(s):

Injection: 20 mg/10 mL (2 mg/mL) solution concentrate in a single-dose vial for dilution and IV infusion.

Dosage

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

Adults

• For pretreatment recommendations, see Full Prescribing Information.

• Recommended dosage is 1 mg/kg every 2 weeks administered as an IV infusion.

• For dosage and administration modifications due to hypersensitivity reactions or infusion-associated reactions (IARs), see Full Prescribing Information.

• For instructions on preparation (including dilution), storage, and administration (including rates for the initial 4–6 infusions for enzyme replacement therapy (ERT)-experienced and ERT-naive patients), see Full Prescribing Information.

Cautions for Pegunigalsidase Alfa-iwxj

Contraindications

• None.

Warnings/Precautions

Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis, have been reported in pegunigalsidase alfa-treated patients. In clinical trials, 14% of patients who received pegunigalsidase alfa-iwxj experienced hypersensitivity reactions. In these trials, 4 patients treated with the drug (3%; 1 naive to enzyme replacement therapy (ERT) and 3 ERT-experienced patients) experienced anaphylaxis during the initial infusion and were positive for anti-pegunigalsidase alfa-iwxj IgE antibodies (referred to as IgE ADA). The risk of pegunigalsidase alfa-related hypersensitivity may be increased in certain patients with pre-existing ADA from prior ERT.

Anaphylaxis (reported as Type I hypersensitivity reaction, hypersensitivity reaction, or bronchospasm) occurred within 5 to 40 minutes of the start of the initial infusion. Signs and symptoms included headache, nausea, vomiting, throat tightness, facial and oral edema, truncal rash, tachycardia, hypotension, rigors, urticaria, intense pruritus, moderate upper airway obstructions, macroglossia, and mild lip edema. Patients received treatment that included epinephrine, antihistamines, and/or systemic corticosteroids.

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

If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue pegunigalsidase alfa immediately and initiate appropriate medical treatment. Consider the risks and benefits of re-administering the drug following severe hypersensitivity reactions (including anaphylaxis). Patients may be rechallenged using slower infusion rates. In patients with severe hypersensitivity reaction, desensitization measures to pegunigalsidase alfa may be considered. If the decision is made to readminister the drug, ensure the patient tolerates the infusion. If the patient tolerates the infusion, the rate may be increased to reach the recommended rate.

If a mild or moderate hypersensitivity reaction occurs, consider temporarily holding the infusion or slowing the infusion rate.

Consider monitoring patients who demonstrate hypersensitivity reactions during pegunigalsidase alfa treatment for the presence of IgG and IgE ADA.

Infusion-associated Reactions

Infusion-associated reactions (IARs) have been reported in pegunigalsidase alfa-treated patients. In clinical trials, 29% of patients who received pegunigalsidase alfa-iwxj experienced one or more IARs, defined as any adverse reaction with onset after start of the infusion and up to 24 hours after the end of infusion. The risk of drug-related IARs may be increased in certain patients with pre-existing ADA from prior ERT. IARs included anaphylaxis reactions during the initial pegunigalsidase alfa-iwxj administration.

In addition to the hypersensitivity reactions described above, other IARs included 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.

Up to 40% of patients were pretreated with diphenhydramine, prednisone, and/or acetaminophen at least once during the clinical trials. Severe reactions in the trials were generally managed with administration of antipyretics, antihistamines, corticosteroids, IV fluids, and/or oxygen. IARs were more frequently observed in pegunigalsidase alfa-iwxj-treated patients who developed IgG anti-drug antibodies (ADA) including patients who had pre-existing IgG ADA. Consider monitoring patients who demonstrate IARs during pegunigalsidase alfa-iwxj treatment for the presence of IgG and IgE ADA .

Patients with advanced Fabry disease may have compromised cardiac function which may predispose them to a higher risk of severe complications from IARs. Closely monitor patients with compromised cardiac function if pegunigalsidase alfa is administered to these patients.

Prior to pegunigalsidase alfa administration, consider pretreatment with antihistamines, antipyretics, and/or corticosteroids to reduce the risk of IARs. However, IARs may still occur in patients after receiving pre-treatment. If a severe IAR occurs, discontinue the drug immediately and initiate appropriate medical treatment. Consider the risks and benefits of re-administering pegunigalsidase alfa-iwxj following a severe IAR. Patients may be rechallenged using slower infusion rates. Once a patient tolerates the infusion, the infusion rate may be increased to reach the recommended infusion rate. If a mild or moderate IAR occurs, consider temporarily holding the infusion or slowing the infusion rate.

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 of pegunigalsidase alfa-iwxj but did not return to baseline by the end of the trial.

Monitor serum creatinine and urinary protein to creatinine ratio. If glomerulonephritis is suspected, discontinue pegunigalsidase alfa until a diagnostic evaluation can be conducted.

Specific Populations

Pregnancy

There are no available data on pegunigalsidase alfa-iwxj use in pregnant females to evaluate a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes; however, as an enzyme replacement, pegunigalsidase alfa is not expected to cause adverse outcomes. Animal reproduction studies have been conducted with pegunigalsidase alfa-iwxj in pregnant rats and rabbits. No adverse effects on embryofetal development were observed in pregnant rats administered IV pegunigalsidase alfa-iwxj twice per week at exposures up to 3.6 times that of the maximum recommended human dose (MRHD) (based on AUC). Maternal toxicity was observed in pregnant rabbits administered IV pegunigalsidase alfa-iwxj twice per week at doses that were ≥3.2 times the MRHD (based on the human equivalent dose).

The estimated background risk of major birth defects and miscarriage in the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

There is a pregnancy safety study for pegunigalsidase alfa-iwxj. If a patient becomes pregnant while receiving the drug, healthcare providers should report the exposure by calling 1-888-661-9260.

Lactation

There are no data on the presence of pegunigalsidase alfa-iwxj in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for pegunigalsidase alfa and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition.

Pediatric Use

The safety and effectiveness of pegunigalsidase alfa-iwxj have not been established in pediatric patients.

Geriatric Use

Clinical trials of pegunigalsidase alfa-iwxj did not include patients 65 years of age and older to determine if they respond differently from younger adult patients.

Patients with Prior Enzyme Replacement Therapy

Patients who received prior ERT are more likely to have pre-existing anti-drug antibodies (ADA) to pegunigalsidase alfa which could be due to the ADA cross-reactivity to pegunigalsidase alfa by prior ERT. When switching from other ERT to pegunigalsidase alfa-iwxj, consider the following:

• Pre-existing ADA may reduce plasma pegunigalsidase alfa concentrations, which may reduce efficacy of the drug.

• The risk of pegunigalsidase alfa-related hypersensitivity and infusion-associated reactions may be increased in certain patients with pre-existing ADA from prior ERT.

Consider monitoring clinical or pharmacodynamic responses (e.g., plasma lyso-Gb3 levels) when switching from agalsidase beta to pegunigalsidase alfa, in patients with pre-existing ADA.

Common Adverse Effects

Most common adverse reactions (≥15%) are infusion-associated reactions, nasopharyngitis, headache, diarrhea, fatigue, nausea, back pain, pain in extremity, and sinusitis.

Drug Interactions

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

• Fabry disease is caused by a deficiency of the lysosomal enzyme α-galactosidase A. Pegunigalsidase alfa provides an exogenous source of α-galactosidase A. Pegunigalsidase alfa is internalized and transported into lysosomes where it is thought to exert enzymatic activity and reduce accumulated globotriaosylceramide (Gb3).

Advice to Patients

• Advise the patient and/or caregiver that reactions related to the infusion may occur during and after pegunigalsidase alfa treatment, including anaphylactic reactions, other serious or severe hypersensitivity reactions, and infusion-associated reactions (IARs). Inform the patient and/or caregiver of the signs and symptoms of hypersensitivity reactions and IARs and to seek immediate medical care should these signs and symptoms occur.

• Advise patients who are exposed to pegunigalsidase alfa-iwxj during pregnancy that there is a pregnancy safety study that monitors pregnancy outcomes. Encourage the patient to report the pregnancy to Chiesi USA, Inc. at 1-888-661-9260.

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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